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Multiple myeloma (MM)

MM is malignant growth of plasma cells, which are terminally differentiated B lymphocytes ¹⁷. The disease is characterized by production of monoclonal immunoglobulin, by anemia, and by destruction of bone. The malignant myeloma cells are usually located in the bone marrow (BM). 

Despite some advances in treatment in recent years, MM still is a persistently fatal disease with a median patient survival time of three to four years from the time of diagnosis. In addition to the dismal prognosis, patients also experience substantial morbidity during the course of the disease. MM therefore continues to be a serious health problem. Standard front-line therapy for patients with MM includes the chemotherapeutic agents melphalan and prednisone, drugs that have been used for this purpose for more than 40 years. Recently, immunomodulatory drugs with putative effect against formation of new blood vessels (e.g., thalidomide), as well as botezomib, a member of an entirely new class of drugs: so-called protesome inhibitors, have shown effects in subsets of patients with MM¹⁸. However, there is an urgent need for better therapy that is targeted at the weak points of MM.

Our understanding of the molecular etiology of MM has increased enormously over the past ten years^5;19. Approximately 50% of patients have translocations affecting the immunoglobulin heavy chain locus on chromosome 14. The translocation partner varies, but close to the breakpoint in the partner chromosome, there is a (putative) oncogene that is placed under transcriptional control of an enhancer normally controlling the immunoglobuline heavy chain gene. The ch14 translocations are believed to be early events in the development of MM, and are also present with roughly the same frequency in the premalignant condition “monoclonal gammopathy of undetermined significance”(MGUS) as in overt MM. (There is only a one percent chance per year of progressing from MGUS to MM, so the majority of MGUS cases never develop into MM.) The other 50% of MM cases do not have ch14 translocations, and the early and crucial genetic aberrations in this group of patients are still unknown, but overall, these cases tend to have hyperdiploidy with trisomy of a several recurrent chromosomes. A common theme in all patients with MM is the expression of various isoforms of the cell cycle regulatory protein cyclin-D⁵.

Myeloma cells usually do not grow for longer periods in vitro, despite addition of rich growth medium and growth factors. It is generally believed that the cells are dependent on currently unknown factors in the microenvironment of the bone marrow for growth and for protection against apoptosis. At the same time the malignant cells exert a profound influence on the same microenvironment. In overt myeloma there is increased bone marrow angiogenesis⁴⁰ and – in most cases – perturbed bone homeostasis^2;3. It has been known for more than three decades that myeloma cells stimulate osteoclasts, the bone-resorbing cells²⁸. A simultaneous reduction in bone formation, leading to an unbalanced bone metabolism with ensuing erosion of bone substance⁴ was also observed many years ago. Factors produced by myeloma cells and either secreted or presented on the cell surface, are believed to be responsible for the perturbed microenvironment, and many candidate factors have been proposed as being responsible for increased bone resorption, with variable experimental documentation.

Role of HGF in the pathogenesis of MM: a mediator of autocrine loops

In 1996 we showed for the first time that myeloma cells express the receptor for HGF, c-Met, and at the same time often produce the ligand HGF⁷. This simultaneous expression of a cytokine and its receptor in the same cell was suggestive of an autocrine stimulatory loop, and we were able to demonstrate that c-Met was indeed activated in the myeloma cell line JJN-3 in an autocrine fashion⁸. Autocrine HGF-driven growth loops have also been demonstrated in other MM cell lines²⁵. Later we showed that high levels of HGF in the serum of a patient with MM at the time of diagnosis was an adverse prognostic sign, a finding that has been confirmed by others^26;32. Recently, we and others have demonstrated that HGF stimulates growth and survival of myeloma cells, and that HGF uses the myeloma marker protein syndecan-1 (CD138) as a co-receptor^13;31. It has also been shown that myeloma cells express HGF activator, an enzyme converting pre-HGF into the active form of the growth factor³⁹. Pre-HGF can also be converted to HGF by urokinase plasminogen activator (uPA)²⁹. This enzyme is also produced by MM cells²⁰. HGF could also be involved in the migration of myeloma cells to the bone marrow⁴¹. HGF is important in promoting adherence of MM cells to fibronectin, a matrix protein in the bone marrow environment²³. Such adhesion is beneficial to the MM cells in the sense that it increases cell proliferation. HGF is also a potent angiogenic factor, and there is a positive correlation between HGF levels in serum and bone marrow angiogenesis in patients with MM, suggesting HGF's role in the excessive angiogenesis seen in these patients¹. In an abstract presented to the 2006 ASH meeting, D. Hose and colleagues presented data showing that among 89 proangiogic genes only HGF was significantly overexpressed in MM cells compared to normal bone marrow plasma cells²⁴.

HGF expression is characteristic of malignant plasma cells and distinguishes MM from other closely related diseases

The first comprehensive gene array study of MM by Zhan et al., comparing gene expression in MM cells with that in normal plasma cells, showed that HGF was the only secreted growth factor on the list of the 70 genes that were the most up-regulated of more than 5000 examined genes⁴⁴. Interestingly, HGF was not only expressed in overt MM, but also in BM plasma cells from a majority of patients with MGUS, indicating that initiation of HGF expression is an early event in the transformation of healthy cells into malignant MM cells (Erming Tian and John D. Shaughnessy Jr., personal communication). A recently published gene array study by Chng et al. showed that expression of HGF together with IL-6, a potent growth factor for MM cells, was characteristic for a subgroup of patients with hyperdiploid MM¹⁰. In another study, using comparative genomic hybridization (aCGH) analysis, recurrent gene copy number alterations were identified, and 47 areas of recurrent gene amplifications were found⁹. HGF was located within a small recurrent amplification that included a total of four genes, and HGF was found to be the only one of those genes with an oncogene-like expression pattern. This amplification was present in more than 40% of patients, and the finding indicates that gene aberrations leading to HGF expression are part of the oncogenic development leading to MM.

In order to identify the gene expression that is important for the specific clinical manifestations of MM, a logical approach would be to compare the gene expression profile of MM cells with that of cells from closely related diseases. This was done with gene array analysis of purified malignant cells from patients with chronic lymphocytic leukemia, Waldenstom macroglobulinemia and MM.¹¹ Again, HGF stood out as one of the genes that characterized MM as opposed to the two other diseases. Interestingly, the HGF receptor c-Met was also on this list of MM-related genes.

Disturbance of key regulators of bone homeostasis in patients with MM

Skeletal tissue in healthy people is constantly undergoing a balanced remodeling process, where osteoclasts resorb bone and are followed by osteoblasts forming bone. Central to this regulation are specific factors that act directly on osteoclasts and are downstream mediators for many of the systemic bone-active factors. It has become clear that osteoblasts play a crucial role in the direct regulation of osteoclast activity. Osteoblasts express the cell surface protein RANKL, which is necessary for osteoclast differentiation⁴³. Furthermore, the osteoblasts express a soluble decoy receptor for RANKL, osteoprotegerin (OPG)³⁵. The balance between the two osteoblast products, RANKL and OPG, seems to be critical for the regulation of bone homeostasis.

We have found that multiple myeloma patients have reduced levels of soluble OPG in bone marrow plasma compared to healthy controls³³ and others have found that there is also an increased expression of RANKL in the MM bone marrow³⁰. OPG contains a heparin binding site and may bind to heparan sulfates on cells in the bone marrow. We have shown that MM cells bind OPG, presumably via the heparan sulfate-containing protein Syndecan-1⁶. Moreover, we found that this binding led to internalization and degradation of OPG by the myeloma cells³⁷, thereby providing one possible explanation for the reduced OPG levels in the bone marrow of multiple myeloma patients.

Inhibition of bone formation is important for skeletal destruction in patients with MM

In patients with MM, the balanced process of bone remodeling is upset, leading to degradation of bone and to skeletal morbidity. Intensive research has been conducted to try to unravel the mechanism causing this bone disease. For several decades, the research focus was on factors leading to untimely activation of osteoclasts, although it had long beenrealized that perturbationin osteoblast function might be equally important⁴. In a mouse model of MM with severe bone disease, osteoblasts were virtually non-existent²². Lately, the focus has moved from osteoclasts to osteoblasts, and several papers have contributed to our understanding of osteoblast inhibition^34;38. Searching for a correlation between gene expression in purified primary MM cells and level of bone disease in the patients, Tian and colleagues identified DKK1, an inhibitor of Wnt signaling, as a prime suspect for the destruction of bone in MM patients³⁸. They found that DKK1 inhibited the differentiation of osteoblast precursors into mature bone-forming osteoblasts. Later studies seem to confirm that DKK1 is linked to excessive bone disease and that it works by inhibiting the formation of osteoblasts^16;42. Interestingly, genes that encode known osteoclast-regulating factors, such as RANKL, RANK, OPG, MIP1, PTHrP, and IL-1, did not show a significant relationto the presence of bone disease²⁷. This is not a proof against these factors as important for bone destruction in MM, but argues against MM cells as the source of them. Similarly, osteoclast-activating factors were conspicuously absent from the list of gene expression that was characteristic for MM cells; as opposed to cells from chronic lymphocytic leukemia and Waldenstom macroglobulinemia¹¹. Bone disease is not a common clinical trait of the latter two diseases, and one would expect the genes that are responsible for this hallmark of MM to be present on the list of genes that define the specific cancer phenotype of MM. Like HGF and c-Met, DKK1 was high up on this list, further supporting the role of DKK1 in promoting the bone disease that is linked to MM.

HGF inhibits bone morphogenetic protein-induced differentiation of mesenchymal stem cells into bone-forming osteoblasts

Since HGF is one of the genes distinguishing malignant plasma cells from healthy plasma cells, and also defines malignant plasma cells as opposed to other closely related malignant cells, it was logical to see whether HGF played a role in bone homeostasis. It had been previously published that HGF induces bone resorption by osteoclasts, but only in the presence of osteoblasts¹⁵. This indirect effect on osteoclasts could be partly through HGF-induced production of IL-11, an osteoclast-stimulating cytokine²¹. Bone morphogenetic proteins (BMP) promote differentiation of osteoblast precursors from mesenchymal stem cells (MSCs) and further maturation into bone forming osteoblasts. Experiments by our group showed that HGF inhibited BMP-induced expression of alkaline phosphatase in human MSCs and in the murine myoid cell line C2C12³⁶. HGF also prevented BMP-induced mineralization by human MSCs. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. Interestingly, HGF promoted proliferation of human MSCs, whereas BMP halted the proliferation. Again, HGF was a key regulator, keeping the cells in a proliferative, undifferentiating state despite the presence of BMP. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation as to how HGF inhibits BMP signaling. These findings support a role of HGF similar to that of DKK1. By preventing MSCs from becoming mature osteoblasts, the osteoblast precursors are arrested in an intermediate stage of differentiation, where they express RANKL, an osteoclast-stimulating protein. Therefore, instead of contributing to bone repair, these cells promote the bone-destruction process: bone homeostasis is no longer balanced. Was there any clinical evidence that HGF really played this role as an osteoblast inhibitor in patients? Yes, the in vitro data were supported by the observation of a significant negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase, in sera from 34 patients with myeloma³⁶.

Targeting HGF hepatocyte growth factor and its receptor c-Met in multiple myeloma

Since expression of HGF seems to be an early oncogenic event in the development of MM, and due to HGF’s many effects on disease manifestations, it might be an attractive target in treatment of MM. A host of new pharmacological inhibitors of c-Met are in the pipelines of the pharmaceutical industry. Possible HGF inhibitors include small molecular drugs and antibodies, as well as naturally occurring splice variants of HGF with antagonistic or partially antagonistic effects on c-Met. NK4 belongs to the latter group: a variant of HGF that lacks part of the full molecule¹². This molecule was shown to block growth of MM cell line cells in a mouse model, an effect that was believed to be a combination of direct anti-proliferative effect of the drug on MM cells, as well as an indirect, anti-angiogenic effect on formation of new blood vessels¹⁴. PHA-665752, a novel pharmacological inhibitor of c-Met from Pfizer belongs to the group of small molecular inhibitors. This molecule prevented HGF-driven autocrine loops in an MM cell line, as well as in freshly isolated MM cells from myeloma patients²⁵. No in vivo data on effects on MM cells of small-molecule inhibitors of c-Met have been published yet, and no clinical trial with c-Met inhibitors has been started so far. However, the data from such studies are sure to be met with great anticipation.

References

1.   Andersen NF, Standal T, Nielsen JL et al. Syndecan-1 and angiogenic cytokines in multiple myeloma: correlation with bone marrow angiogenesis and survival. Br.J.Haematol. 2005;128:210-217.

2.   Bataille R, Chappard D, Basle M. Excessive bone resorption in human plasmacytomas: direct induction by tumour cells in vivo. Br.J.Haematol. 1995;90:721-724.

3.   Bataille R, Chappard D, Klein B. Mechanisms of bone lesions in multiple myeloma. Hematol.Oncol.Clin.North Am. 1992;6:285-295.

4.   Bataille R, Chappard D, Marcelli C et al. Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease. J.Clin.Oncol. 1989;7:1909-1914.

5.   Bergsagel PL, Kuehl WM. Molecular pathogenesis and a consequent classification of multiple myeloma. J.Clin.Oncol. 2005;23:6333-6338.

6.   Borset M, Hjertner O, Yaccoby S, Epstein J, Sanderson RD. Syndecan-1 is targeted to the uropods of polarized myeloma cells where it promotes adhesion and sequesters heparin-binding proteins. Blood 2000;96:2528-2536.

7.   Borset M, Hjorth-Hansen H, Seidel C, Sundan A, Waage A. Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood 1996;88:3998-4004.

8.   Borset M, Lien E, Espevik T et al. Concomitant expression of hepatocyte growth factor/scatter factor and the receptor c-MET in human myeloma cell lines. J.Biol.Chem. 1996;271:24655-24661.

9.   Carrasco DR, Tonon G, Huang Y et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 2006;9:313-325.

10.   Chng WJ, Kumar S, Vanwier S et al. Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling. Cancer Res. 2007;67:2982-2989.

11.   Chng WJ, Schop RF, Price-Troska T et al. Gene-expression profiling of Waldenstrom macroglobulinemia reveals a phenotype more similar to chronic lymphocytic leukemia than multiple myeloma. Blood 2006;108:2755-2763.

12.   Date K, Matsumoto K, Shimura H, Tanaka M, Nakamura T. HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. FEBS Lett. 1997;420:1-6.

13.   Derksen PW, Keehnen RM, Evers LM et al. Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. Blood 2002;99:1405-1410.

14.   Du W, Hattori Y, Yamada T et al. NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells in vivo; molecular targeting of angiogenic growth factor. Blood 2006

15.   Grano M, Galimi F, Zambonin G et al. Hepatocyte growth factor is a coupling factor for osteoclasts and osteoblasts in vitro. Proc Natl Acad Sci USA 1996;93:7644-7648.

16.   Haaber J, Abildgaard N, Knudsen LM et al. Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis. Br.J.Haematol. 2007

17.   Hallek, M., Bergsagel, P. L., and Anderson, K. C. Multiple myeloma: Increasing evidence for a multistep transformation process. Blood 91, 3-21. 1998.

18.   Hayden PJ, Mitsiades CS, Anderson KC, Richardson PG. Novel therapies in myeloma. Curr.Opin.Hematol. 2007;14:609-615.

19.   Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104:607-618.

20.   Hjertner O, Qvigstad G, Hjorth-Hansen H et al. Expression of urokinase plasminogen activator and the urokinase plasminogen activator receptor in myeloma cells. Br.J.Haematol. 2000;109:815-822.

21.   Hjertner O, Torgersen ML, Seidel C et al. Hepatocyte growth factor (HGF) induces interleukin-11 secretion from osteoblasts: a possible role for HGF in myeloma-associated osteolytic bone disease. Blood 1999;94:3883-3888.

22.   Hjorth-Hansen H, Seifert MF, Borset M et al. Marked osteoblastopenia and reduced bone formation in a model of multiple myeloma bone disease in severe combined immunodeficiency mice. J.Bone Miner.Res. 1999;14:256-263.

23.   Holt RU, Baykov V, Ro TB et al. Human myeloma cells adhere to fibronectin in response to hepatocyte growth factor. Haematologica 2005;90:479-488.

24.   Hose D, Devos J, Heib C et al. Angiogenesis in multiple myeloma (MM): Angiogenic switch or reflexion of plasma cell number? A gene expression based survey in primary myeloma cells and the bone marrow microenvironment. Blood 2006;108:972A-973A.

25.   Hov H, Holt RU, Ro TB et al. A selective c-met inhibitor blocks an autocrine hepatocyte growth factor growth loop in ANBL-6 cells and prevents migration and adhesion of myeloma cells. Clin.Cancer Res. 2004;10:6686-6694.

26.   Iwasaki T, Hamano T, Ogata A et al. Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma. Br.J.Haematol. 2002;116:796-802.

27.   Lu CM. DKK1 in multiple myeloma. N.Engl.J.Med. 2004;350:1464-1466.

28.   Mundy GR, Raisz LG, Cooper RA, Schechter GP, Salmon SE. Evidence for the Secretion of an Osteoclast Stimulating Factor in Myeloma. N.Engl.J.Med. 1974;291:1041-1046.

29.   Naldini L, Vigna E, Bardelli A et al. Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction. J.Biol.Chem. 1995;270:603-611.

30.   Pearse RN, Sordillo EM, Yaccoby S et al. Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc.Natl.Acad.Sci.U.S.A 2001;98:11581-11586.

31.   Seidel C, Borset M, Hjertner O et al. High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity. Blood 2000;96:3139-3146.

32.   Seidel C, Borset M, Turesson I et al. Elevated serum concentrations of hepatocyte growth factor in patients with multiple myeloma. The Nordic Myeloma Study Group. Blood 1998;91:806-812.

33.   Seidel C, Hjertner O, Abildgaard N et al. Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease. Blood 2001;98:2269-2271.

34.   Silvestris F, Cafforio P, Tucci M, Grinello D, Dammacco F. Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease. Br.J.Haematol. 2003;122:39-52.

35.   Simonet WS, Lacey DL, Dunstan CR et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997;89:309-319.

36.   Standal T, Abildgaard N, Fagerli UM et al. HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood 2006

37.   Standal T, Seidel C, Hjertner O et al. Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 2002;100:3002-3007.

38.   Tian E, Zhan F, Walker R et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N.Engl.J.Med. 2003;349:2483-2494.

39.   Tjin EP, Derksen PW, Kataoka H, Spaargaren M, Pals ST. Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by secreting the serine protease HGF-activator. Blood 2004;104:2172-2175.

40.   Vacca A, Ribatti D, Roncali L et al. Bone-Marrow Angiogenesis and Progression in Multiple Myeloma. Br.J.Haematol. 1994;87:503-508.

41.   Vande B, I, Asosingh K, Allegaert V et al. Bone marrow endothelial cells increase the invasiveness of human multiple myeloma cells through upregulation of MMP-9: evidence for a role of hepatocyte growth factor. Leukemia 2004;18:976-982.

42.   Yaccoby S, Ling W, Zhan F et al. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood 2007;109:2106-2111.

43.   Yasuda H, Shima N, Nakagawa N et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc.Natl.Acad.Sci.U.S.A 1998;95:3597-3602.

44.   Zhan F, Hardin J, Kordsmeier B et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 2002;99:1745-1757.

" ["~DETAIL_TEXT"]=> string(25510) "

Multiple myeloma (MM)

MM is malignant growth of plasma cells, which are terminally differentiated B lymphocytes ¹⁷. The disease is characterized by production of monoclonal immunoglobulin, by anemia, and by destruction of bone. The malignant myeloma cells are usually located in the bone marrow (BM). 

Despite some advances in treatment in recent years, MM still is a persistently fatal disease with a median patient survival time of three to four years from the time of diagnosis. In addition to the dismal prognosis, patients also experience substantial morbidity during the course of the disease. MM therefore continues to be a serious health problem. Standard front-line therapy for patients with MM includes the chemotherapeutic agents melphalan and prednisone, drugs that have been used for this purpose for more than 40 years. Recently, immunomodulatory drugs with putative effect against formation of new blood vessels (e.g., thalidomide), as well as botezomib, a member of an entirely new class of drugs: so-called protesome inhibitors, have shown effects in subsets of patients with MM¹⁸. However, there is an urgent need for better therapy that is targeted at the weak points of MM.

Our understanding of the molecular etiology of MM has increased enormously over the past ten years^5;19. Approximately 50% of patients have translocations affecting the immunoglobulin heavy chain locus on chromosome 14. The translocation partner varies, but close to the breakpoint in the partner chromosome, there is a (putative) oncogene that is placed under transcriptional control of an enhancer normally controlling the immunoglobuline heavy chain gene. The ch14 translocations are believed to be early events in the development of MM, and are also present with roughly the same frequency in the premalignant condition “monoclonal gammopathy of undetermined significance”(MGUS) as in overt MM. (There is only a one percent chance per year of progressing from MGUS to MM, so the majority of MGUS cases never develop into MM.) The other 50% of MM cases do not have ch14 translocations, and the early and crucial genetic aberrations in this group of patients are still unknown, but overall, these cases tend to have hyperdiploidy with trisomy of a several recurrent chromosomes. A common theme in all patients with MM is the expression of various isoforms of the cell cycle regulatory protein cyclin-D⁵.

Myeloma cells usually do not grow for longer periods in vitro, despite addition of rich growth medium and growth factors. It is generally believed that the cells are dependent on currently unknown factors in the microenvironment of the bone marrow for growth and for protection against apoptosis. At the same time the malignant cells exert a profound influence on the same microenvironment. In overt myeloma there is increased bone marrow angiogenesis⁴⁰ and – in most cases – perturbed bone homeostasis^2;3. It has been known for more than three decades that myeloma cells stimulate osteoclasts, the bone-resorbing cells²⁸. A simultaneous reduction in bone formation, leading to an unbalanced bone metabolism with ensuing erosion of bone substance⁴ was also observed many years ago. Factors produced by myeloma cells and either secreted or presented on the cell surface, are believed to be responsible for the perturbed microenvironment, and many candidate factors have been proposed as being responsible for increased bone resorption, with variable experimental documentation.

Role of HGF in the pathogenesis of MM: a mediator of autocrine loops

In 1996 we showed for the first time that myeloma cells express the receptor for HGF, c-Met, and at the same time often produce the ligand HGF⁷. This simultaneous expression of a cytokine and its receptor in the same cell was suggestive of an autocrine stimulatory loop, and we were able to demonstrate that c-Met was indeed activated in the myeloma cell line JJN-3 in an autocrine fashion⁸. Autocrine HGF-driven growth loops have also been demonstrated in other MM cell lines²⁵. Later we showed that high levels of HGF in the serum of a patient with MM at the time of diagnosis was an adverse prognostic sign, a finding that has been confirmed by others^26;32. Recently, we and others have demonstrated that HGF stimulates growth and survival of myeloma cells, and that HGF uses the myeloma marker protein syndecan-1 (CD138) as a co-receptor^13;31. It has also been shown that myeloma cells express HGF activator, an enzyme converting pre-HGF into the active form of the growth factor³⁹. Pre-HGF can also be converted to HGF by urokinase plasminogen activator (uPA)²⁹. This enzyme is also produced by MM cells²⁰. HGF could also be involved in the migration of myeloma cells to the bone marrow⁴¹. HGF is important in promoting adherence of MM cells to fibronectin, a matrix protein in the bone marrow environment²³. Such adhesion is beneficial to the MM cells in the sense that it increases cell proliferation. HGF is also a potent angiogenic factor, and there is a positive correlation between HGF levels in serum and bone marrow angiogenesis in patients with MM, suggesting HGF's role in the excessive angiogenesis seen in these patients¹. In an abstract presented to the 2006 ASH meeting, D. Hose and colleagues presented data showing that among 89 proangiogic genes only HGF was significantly overexpressed in MM cells compared to normal bone marrow plasma cells²⁴.

HGF expression is characteristic of malignant plasma cells and distinguishes MM from other closely related diseases

The first comprehensive gene array study of MM by Zhan et al., comparing gene expression in MM cells with that in normal plasma cells, showed that HGF was the only secreted growth factor on the list of the 70 genes that were the most up-regulated of more than 5000 examined genes⁴⁴. Interestingly, HGF was not only expressed in overt MM, but also in BM plasma cells from a majority of patients with MGUS, indicating that initiation of HGF expression is an early event in the transformation of healthy cells into malignant MM cells (Erming Tian and John D. Shaughnessy Jr., personal communication). A recently published gene array study by Chng et al. showed that expression of HGF together with IL-6, a potent growth factor for MM cells, was characteristic for a subgroup of patients with hyperdiploid MM¹⁰. In another study, using comparative genomic hybridization (aCGH) analysis, recurrent gene copy number alterations were identified, and 47 areas of recurrent gene amplifications were found⁹. HGF was located within a small recurrent amplification that included a total of four genes, and HGF was found to be the only one of those genes with an oncogene-like expression pattern. This amplification was present in more than 40% of patients, and the finding indicates that gene aberrations leading to HGF expression are part of the oncogenic development leading to MM.

In order to identify the gene expression that is important for the specific clinical manifestations of MM, a logical approach would be to compare the gene expression profile of MM cells with that of cells from closely related diseases. This was done with gene array analysis of purified malignant cells from patients with chronic lymphocytic leukemia, Waldenstom macroglobulinemia and MM.¹¹ Again, HGF stood out as one of the genes that characterized MM as opposed to the two other diseases. Interestingly, the HGF receptor c-Met was also on this list of MM-related genes.

Disturbance of key regulators of bone homeostasis in patients with MM

Skeletal tissue in healthy people is constantly undergoing a balanced remodeling process, where osteoclasts resorb bone and are followed by osteoblasts forming bone. Central to this regulation are specific factors that act directly on osteoclasts and are downstream mediators for many of the systemic bone-active factors. It has become clear that osteoblasts play a crucial role in the direct regulation of osteoclast activity. Osteoblasts express the cell surface protein RANKL, which is necessary for osteoclast differentiation⁴³. Furthermore, the osteoblasts express a soluble decoy receptor for RANKL, osteoprotegerin (OPG)³⁵. The balance between the two osteoblast products, RANKL and OPG, seems to be critical for the regulation of bone homeostasis.

We have found that multiple myeloma patients have reduced levels of soluble OPG in bone marrow plasma compared to healthy controls³³ and others have found that there is also an increased expression of RANKL in the MM bone marrow³⁰. OPG contains a heparin binding site and may bind to heparan sulfates on cells in the bone marrow. We have shown that MM cells bind OPG, presumably via the heparan sulfate-containing protein Syndecan-1⁶. Moreover, we found that this binding led to internalization and degradation of OPG by the myeloma cells³⁷, thereby providing one possible explanation for the reduced OPG levels in the bone marrow of multiple myeloma patients.

Inhibition of bone formation is important for skeletal destruction in patients with MM

In patients with MM, the balanced process of bone remodeling is upset, leading to degradation of bone and to skeletal morbidity. Intensive research has been conducted to try to unravel the mechanism causing this bone disease. For several decades, the research focus was on factors leading to untimely activation of osteoclasts, although it had long beenrealized that perturbationin osteoblast function might be equally important⁴. In a mouse model of MM with severe bone disease, osteoblasts were virtually non-existent²². Lately, the focus has moved from osteoclasts to osteoblasts, and several papers have contributed to our understanding of osteoblast inhibition^34;38. Searching for a correlation between gene expression in purified primary MM cells and level of bone disease in the patients, Tian and colleagues identified DKK1, an inhibitor of Wnt signaling, as a prime suspect for the destruction of bone in MM patients³⁸. They found that DKK1 inhibited the differentiation of osteoblast precursors into mature bone-forming osteoblasts. Later studies seem to confirm that DKK1 is linked to excessive bone disease and that it works by inhibiting the formation of osteoblasts^16;42. Interestingly, genes that encode known osteoclast-regulating factors, such as RANKL, RANK, OPG, MIP1, PTHrP, and IL-1, did not show a significant relationto the presence of bone disease²⁷. This is not a proof against these factors as important for bone destruction in MM, but argues against MM cells as the source of them. Similarly, osteoclast-activating factors were conspicuously absent from the list of gene expression that was characteristic for MM cells; as opposed to cells from chronic lymphocytic leukemia and Waldenstom macroglobulinemia¹¹. Bone disease is not a common clinical trait of the latter two diseases, and one would expect the genes that are responsible for this hallmark of MM to be present on the list of genes that define the specific cancer phenotype of MM. Like HGF and c-Met, DKK1 was high up on this list, further supporting the role of DKK1 in promoting the bone disease that is linked to MM.

HGF inhibits bone morphogenetic protein-induced differentiation of mesenchymal stem cells into bone-forming osteoblasts

Since HGF is one of the genes distinguishing malignant plasma cells from healthy plasma cells, and also defines malignant plasma cells as opposed to other closely related malignant cells, it was logical to see whether HGF played a role in bone homeostasis. It had been previously published that HGF induces bone resorption by osteoclasts, but only in the presence of osteoblasts¹⁵. This indirect effect on osteoclasts could be partly through HGF-induced production of IL-11, an osteoclast-stimulating cytokine²¹. Bone morphogenetic proteins (BMP) promote differentiation of osteoblast precursors from mesenchymal stem cells (MSCs) and further maturation into bone forming osteoblasts. Experiments by our group showed that HGF inhibited BMP-induced expression of alkaline phosphatase in human MSCs and in the murine myoid cell line C2C12³⁶. HGF also prevented BMP-induced mineralization by human MSCs. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. Interestingly, HGF promoted proliferation of human MSCs, whereas BMP halted the proliferation. Again, HGF was a key regulator, keeping the cells in a proliferative, undifferentiating state despite the presence of BMP. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation as to how HGF inhibits BMP signaling. These findings support a role of HGF similar to that of DKK1. By preventing MSCs from becoming mature osteoblasts, the osteoblast precursors are arrested in an intermediate stage of differentiation, where they express RANKL, an osteoclast-stimulating protein. Therefore, instead of contributing to bone repair, these cells promote the bone-destruction process: bone homeostasis is no longer balanced. Was there any clinical evidence that HGF really played this role as an osteoblast inhibitor in patients? Yes, the in vitro data were supported by the observation of a significant negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase, in sera from 34 patients with myeloma³⁶.

Targeting HGF hepatocyte growth factor and its receptor c-Met in multiple myeloma

Since expression of HGF seems to be an early oncogenic event in the development of MM, and due to HGF’s many effects on disease manifestations, it might be an attractive target in treatment of MM. A host of new pharmacological inhibitors of c-Met are in the pipelines of the pharmaceutical industry. Possible HGF inhibitors include small molecular drugs and antibodies, as well as naturally occurring splice variants of HGF with antagonistic or partially antagonistic effects on c-Met. NK4 belongs to the latter group: a variant of HGF that lacks part of the full molecule¹². This molecule was shown to block growth of MM cell line cells in a mouse model, an effect that was believed to be a combination of direct anti-proliferative effect of the drug on MM cells, as well as an indirect, anti-angiogenic effect on formation of new blood vessels¹⁴. PHA-665752, a novel pharmacological inhibitor of c-Met from Pfizer belongs to the group of small molecular inhibitors. This molecule prevented HGF-driven autocrine loops in an MM cell line, as well as in freshly isolated MM cells from myeloma patients²⁵. No in vivo data on effects on MM cells of small-molecule inhibitors of c-Met have been published yet, and no clinical trial with c-Met inhibitors has been started so far. However, the data from such studies are sure to be met with great anticipation.

References

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Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (<strong>МК</strong>), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов. </p> <p class="bodytext"><strong>HGF является фактором аутокринной стимуляции МК.</strong>  <strong>Экспрессия </strong><strong>HGF характерна для МК и отличает ММ от родственных опухолей. </strong>МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген <em>HGF</em> является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена <em>HGF</em> была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген <em>HGF</em> включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.<br /><br /><strong>Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. </strong>Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.<br /><br />До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (<em>RANKL, </em><em>RANK, </em><em>OPG, </em><em>MIP1</em><em><img v:shapes="_x0000_i1025" src="file:///C:%5CDOKUME~1%5COksana%5CLOKALE~1%5CTemp%5Cmsohtml1%5C01%5Cclip_image002.gif" width="8" height="6" alt="" />, </em><em>PTHrP,</em> и <em>IL1)</em>, а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.<br /><br /><strong>HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (</strong><strong>BMP). </strong>HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ. </p> <p class="bodytext"><strong>HGF и </strong><strong>c-</strong><strong>Met как потенциальные мишени терапии. </strong>Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(129) "Роль фактора роста гепатоцитов (HGF) в патогенезе множественной миеломы" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(129) "Роль фактора роста гепатоцитов (HGF) в патогенезе множественной миеломы" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(129) "Роль фактора роста гепатоцитов (HGF) в патогенезе множественной миеломы" ["SECTION_META_TITLE"]=> string(129) "Роль фактора роста гепатоцитов (HGF) в патогенезе множественной миеломы" ["SECTION_META_KEYWORDS"]=> string(129) "Роль фактора роста гепатоцитов (HGF) в патогенезе множественной миеломы" ["SECTION_META_DESCRIPTION"]=> string(129) "Роль фактора роста гепатоцитов (HGF) в патогенезе множественной миеломы" ["SECTION_PICTURE_FILE_ALT"]=> 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["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10390" ["VALUE"]=> array(2) { ["TEXT"]=> string(113) "<p class="Autor">М. Борсет, Т. Стандал, А. Вааге, А. Сундан</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(91) "

М. Борсет, Т. Стандал, А. Вааге, А. Сундан

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10407" ["VALUE"]=> array(2) { ["TEXT"]=> string(10157) "<p class="bodytext">Множественная миелома (<strong>ММ</strong>)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (<strong>МК</strong>), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов. </p> <p class="bodytext"><strong>HGF является фактором аутокринной стимуляции МК.</strong>  <strong>Экспрессия </strong><strong>HGF характерна для МК и отличает ММ от родственных опухолей. </strong>МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген <em>HGF</em> является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена <em>HGF</em> была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген <em>HGF</em> включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.<br /><br /><strong>Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. </strong>Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.<br /><br />До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (<em>RANKL, </em><em>RANK, </em><em>OPG, </em><em>MIP1</em><em><img v:shapes="_x0000_i1025" src="file:///C:%5CDOKUME~1%5COksana%5CLOKALE~1%5CTemp%5Cmsohtml1%5C01%5Cclip_image002.gif" width="8" height="6" alt="" />, </em><em>PTHrP,</em> и <em>IL1)</em>, а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.<br /><br /><strong>HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (</strong><strong>BMP). </strong>HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ. </p> <p class="bodytext"><strong>HGF и </strong><strong>c-</strong><strong>Met как потенциальные мишени терапии. </strong>Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(9747) "

Множественная миелома (ММ)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (МК), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов.

HGF является фактором аутокринной стимуляции МК.  Экспрессия HGF характерна для МК и отличает ММ от родственных опухолей. МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген HGF является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена HGF была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген HGF включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.

Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.

До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (RANKL, RANK, OPG, MIP1, PTHrP, и IL1), а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.

HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (BMP). HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ.

HGF и c-Met как потенциальные мишени терапии. Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес.

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Magne Børset^1,2, Therese Standal¹, Anders Waage^1,3 and Anders Sundan¹

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¹Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; ²Department of Immunology and Transfusion medicine, St. Olavs University Hospital, Trondheim, Norway; ³ Department of Hematology, St. Olavs University Hospital, Trondheim, Norway.

Corresponding author:
Magne Børset, Norwegian University of Science and Technology, Faculty of Medicine, Department of Cancer Research and Molecular Medicine, Medical Technical Research Center, N-7489 Trondheim, Norway

Telephone: + 47 72573038,
Fax: + 47 73598801,
E-mail: magne.borset@ntnu.no

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Magne Børset^1,2, Therese Standal¹, Anders Waage^1,3 and Anders Sundan¹

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Magne Børset^1,2, Therese Standal¹, Anders Waage^1,3 and Anders Sundan¹

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HGF is emerging as a cytokine with an important role in the pathophysiology of multiple myeloma. Originally identified and described as a growth factor for hepatocytes, HGF was later found to have mitogenic, motogenic, or morphogenic effects on several cell types through its interaction with the tyrosine kinase receptor c-Met. This cytokine–receptor pair is implicated in the development and promotion of several types of cancer. The expression of both HGF and c-Met by myeloma cells is one of the traits distinguishing these cells from healthy plasma cells, and seems to be an early step in tumor development. HGF and c-Met have an effect on proliferation, migration, and adhesion of myeloma cells; and research suggests that myeloma cell-produced HGF is an important factor in angiogenesis and bone destruction seen in the majority of patients with multiple myeloma.

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HGF is emerging as a cytokine with an important role in the pathophysiology of multiple myeloma. Originally identified and described as a growth factor for hepatocytes, HGF was later found to have mitogenic, motogenic, or morphogenic effects on several cell types through its interaction with the tyrosine kinase receptor c-Met. This cytokine–receptor pair is implicated in the development and promotion of several types of cancer. The expression of both HGF and c-Met by myeloma cells is one of the traits distinguishing these cells from healthy plasma cells, and seems to be an early step in tumor development. HGF and c-Met have an effect on proliferation, migration, and adhesion of myeloma cells; and research suggests that myeloma cell-produced HGF is an important factor in angiogenesis and bone destruction seen in the majority of patients with multiple myeloma.

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¹Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; ²Department of Immunology and Transfusion medicine, St. Olavs University Hospital, Trondheim, Norway; ³ Department of Hematology, St. Olavs University Hospital, Trondheim, Norway.

Corresponding author:
Magne Børset, Norwegian University of Science and Technology, Faculty of Medicine, Department of Cancer Research and Molecular Medicine, Medical Technical Research Center, N-7489 Trondheim, Norway

Telephone: + 47 72573038,
Fax: + 47 73598801,
E-mail: magne.borset@ntnu.no

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¹Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; ²Department of Immunology and Transfusion medicine, St. Olavs University Hospital, Trondheim, Norway; ³ Department of Hematology, St. Olavs University Hospital, Trondheim, Norway.

Corresponding author:
Magne Børset, Norwegian University of Science and Technology, Faculty of Medicine, Department of Cancer Research and Molecular Medicine, Medical Technical Research Center, N-7489 Trondheim, Norway

Telephone: + 47 72573038,
Fax: + 47 73598801,
E-mail: magne.borset@ntnu.no

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М. Борсет, Т. Стандал, А. Вааге, А. Сундан

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["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10407" ["VALUE"]=> array(2) { ["TEXT"]=> string(10157) "<p class="bodytext">Множественная миелома (<strong>ММ</strong>)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (<strong>МК</strong>), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов. </p> <p class="bodytext"><strong>HGF является фактором аутокринной стимуляции МК.</strong>  <strong>Экспрессия </strong><strong>HGF характерна для МК и отличает ММ от родственных опухолей. </strong>МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген <em>HGF</em> является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена <em>HGF</em> была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген <em>HGF</em> включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.<br /><br /><strong>Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. </strong>Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.<br /><br />До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (<em>RANKL, </em><em>RANK, </em><em>OPG, </em><em>MIP1</em><em><img v:shapes="_x0000_i1025" src="file:///C:%5CDOKUME~1%5COksana%5CLOKALE~1%5CTemp%5Cmsohtml1%5C01%5Cclip_image002.gif" width="8" height="6" alt="" />, </em><em>PTHrP,</em> и <em>IL1)</em>, а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.<br /><br /><strong>HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (</strong><strong>BMP). </strong>HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ. </p> <p class="bodytext"><strong>HGF и </strong><strong>c-</strong><strong>Met как потенциальные мишени терапии. </strong>Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(9747) "

Множественная миелома (ММ)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (МК), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов.

HGF является фактором аутокринной стимуляции МК.  Экспрессия HGF характерна для МК и отличает ММ от родственных опухолей. МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген HGF является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена HGF была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген HGF включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.

Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.

До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (RANKL, RANK, OPG, MIP1, PTHrP, и IL1), а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.

HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (BMP). HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ.

HGF и c-Met как потенциальные мишени терапии. Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес.

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Множественная миелома (ММ)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (МК), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов.

HGF является фактором аутокринной стимуляции МК.  Экспрессия HGF характерна для МК и отличает ММ от родственных опухолей. МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген HGF является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена HGF была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген HGF включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.

Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.

До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (RANKL, RANK, OPG, MIP1, PTHrP, и IL1), а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.

HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (BMP). HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ.

HGF и c-Met как потенциальные мишени терапии. Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес.

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Introduction

The birth of every newborn human produces a precious byproduct. In the expelled placenta there is a sufficient amount of Cord Blood (CB), in which there is abundance of hematopoietic elements. In 1988 Elaine Gluckman showed that a Hematopoietic Stem Cell Transplantation (HSCT) can succeed by using CB as a source for the graft [33]. Gradually thousands of such transplantations began to be performed all over the world. Up until recently most transplantations with CB had been done in children; however the main progress in the field in the last 2 years has been achieved in adults with hematological malignancies. But even though HSCT is still the major indication for using CB, there is a growing interest in finding it as a source for non-hematopoietic stem cells (SC) for regenerative medicine, gene therapy vector, and other potential uses.

Collection of cord blood in the delivery room

CB's collection is done in the delivery room. The blood is drawn from the umbilical vein, before or after the expulsion of the placenta.

The main advantage of the collection process of CB is its simplicity. It poses no danger and causes no pain to the laboring mother or the newborn. Before the collection itself consent is given by the mother. Some centers also addend a short interview, and others use questionnaires for identification of high risk mothers [29].

Cryopreservation

After its collection CB undergoes cryopreservation. The most widely used method is the one reported by Rubinstein et al [89]. It is based on red blood cell depletion and volume reduction. At the end of the process the total volume of each unit is 25 milliliters.

Cord blood public banks

Before freezing, CB samples undergo several tests. Every unit is screened for infectious agents, and in some banks, for relevant inherited diseases. HLA typing is usually done for A, B in serology, and DR in DNA. Some diversity exists between banks with regard to the routine tests that each unit undergoes. Additional samples are maintained in small plastic segments attached to the frozen unit in case future tests are needed.

It is estimated that today there are about 250,000 CB units frozen in 35 banks in 21 countries [14]. CB banking is facing some challenges. The first is the scarcity of space, which is dealt with by volume reduction methods and selection of presumed optimal units, usually with higher volume. Another issue is the uncertainty regarding the period of time which units can be preserved without damage to the viability of the cells. The banks also face ethical issues. For example, if an adult disagrees with the usage of CB that his parents gave consent for donation for decades ago, what is the value of such consent? Another concern is the fate of the information that is stored in CB banks regarding donors' infectious status or the presence of genetic diseases. Is this sensitive data protected as it should be? The need for follow up is understandable, but it could also affect the diversity of ethnic pool of the donors. The ability to detect the donors might also put their families under pressure to donate more cells when the need for it might come.

The importance of public CB banking gained an official acknowledgment when the American congress decided to add $30 million for collection of an additional 150,000 units.

Apart from the above, one of the most controversial issues is private CB banking.

Private cord blood banks

This is an ever growing trend that emerged in the early 90s. These private firms offer storage of CB units against a future need for autologous or related allogeneic transplantations. Questions have been recently being raised  about whether overanxious parents are truly aware that there are no indications today for autologous cord blood transplantation (CBT). Are they informed about the slim chances for a family of ever needing a sibling CBT, and do they know about the lack of knowledge regarding the how long CB's hematopoietic SC preserve their viability while frozen?

The pace of collection in the private banks exceeds the one in the public banks. It is estimated that approximately 600,000 units are frozen privately. These facts raise questions about whether this limited source of hematopoietic SC should not be solely in public hands.

The unique properties of cord blood

Aspirates of bone marrow (BM), or the more recently used Peripheral Blood Stem Cell Collection (PBSC) product, have been traditionally used as sources for HSCT. CB has a few different qualities.

It had long been acknowledged that the more nucleated cells in a graft, the better the chances of engraftment. When taking CB into account as a hematopoietic SC source for transplantation, it is evident that it has fewer nucleated cells than other sources. Each aspirate of BM yields 750-1000 milliliters. This volume usually gives a nucleated cell dose of 2x10⁸/kg for an average weight adult. The product of PBSC yields similar number of SC. The volume of a typical CB unit is usually only 75-150 milliliters. The nucleated cells dose is only one tenth of the BM dose, usually no more than 2x10⁷/kg, for an adult.

Another relevant component of the graft that marks the difference between CB and BM is T cells. These are considered to have a deleterious effect regarding the immune response of the graft against the recipient. The total dose of T cells (CD3⁺ cells) in CB units is less than a fifth of the amount in BM grafts. When comparing it to mobilized peripheral blood grafts, CB units have less than 2% of T cell dose. But while less hematopoietic SC in CB is a setback regarding HSCT, the scarceness of T cells is an advantage, with respect to the risk of graft versus host disease (GVHD) [9, 12].

The low number of SC in CB graft is masked by an excellent proliferative response. When these cells are in a dormant state and cytokines are introduced into their environment, they expand much better than hematopoietic SC of BM. This trait enables CB to produce full hematopoietic recovery of BM in myeloablated recipients [64, 57].

The naïve nature of the immune system's cells in CB is a different issue.

The lymphocytes in CB grafts have a more tolerant nature [73, 82, 83, 88, 22, 32]. Other components of the system, such as dendritic and Natural Killer cells also have different properties, when compared to BM or adult peripheral blood [56, 45, 94, 17, 59, 23]. Because of this, CB allows greater human leukocyte antigen (HLA) disparities in transplantations, with less rejection and lower rates of GVHD.

Cord blood transplantation, clinical experience

Reports on a series of CBT started to appear at the beginning of the end of the 1990s and at the beginning of the third millennium. These were based mostly on the American and the European registries, with some reports from Japanese and other institutes. Table 1 & 2 summarizes the largest clinical trials of CBT using unrelated donors [89, 34, 101, 68, 60, 49, 50, 85, 97, 62]. A few important concepts could be built upon results from these works. First was the notion that CB, with its limited nucleated cells dose, can produce full hematopoietic reconstitution after myeloablative conditioning. Secondly, the median time of myeloid recovery in CBT ranged from 22 to 33 days. This is a far longer period than the time in bone marrow transplantation (BMT) experience. When BM aplasia is prolonged, morbidity and mortality rates rise. The third notion was that despite the existence of a significant proportion of HLA disparity between donors and recipients, rejection and GVHD rates were surprisingly low.

So these trials proved that CB is a legitimate source for HSCT, with problematic engraftment kinetics, but less restriction to HLA matching when compared to BM.

Since each placenta contains a limited volume of blood, it follows that there is also a limited amount of nucleated cells per unit. The correlation between nucleated cell dose and transplantation outcomes was evaluated. A positive impact of cell dose on time to engraftment, and hence the overall survival, has been demonstrated in both pediatric and adult series. It is probably agreed that the minimal acceptable threshold of nucleated cells dose should be 1.5x10⁷ nucleated cells/kg, but an association between dose of 3.7x10⁷ nucleated cells/kg and more and faster time to neutrophil engraftment was suggested by the Eurocord [34, 3]. The New York Blood Group reported that 2.5x10⁷ nucleated cells/kg is the minimal threshold for transplantation [89].

Historically CD34⁺ cells counts were not part of the tests done routinely on CB units. But it is reasonable to assume that it might be so in the near future. Counting nucleated cells involves many cells that do not contribute to the engraftment potential. And indeed, Wagner et al has shown a correlation between CD34⁺ dose of 1.7x10⁵cell/kg and higher to rapid neutrophil engraftment and probability of engraftment [101].

Related donor transplants

Although the first CBT was done from a sibling donor, related donors transplants are used less frequently in this setup. For the cure of malignant diseases CB from a sibling could be used if there is a perfect timing of a birth in the family, or a if a CB unit had been cryopreserved earlier, either by chance or by intention. In non-malignant disease there is usually more time. Families that are aware of CB as a source for transplantation might act on time when births are due.

Several reports of large series of trials have been published. These series have demonstrated that CB is a valid therapeutic option as a source for pediatric transplantation for malignant and non-malignant diseases. The probability for survival at 1 year was 0.63 (95% CI: 0.57-0.69) in the Eurocord study, and 0.61 (95% CI: 0.81-0.49) at 2 years in the ICBTR study [89, 35].

The largest of the series is a joint European and American work that compared 113 related donor CBT in children with 2052 cases of related donor BMT. Neutrophils engraftment in the CB group occurred at a median time of 26 days, compared to 18 in the BM group. Probability of myeloid recovery at day 60 was 0.89 and 0.98 in the CB and BM respectively. Children who received CB had a significantly lower risk of both AGVHD and CGVHD than those who were transplanted from BM (relative risk 0.41; p=0.001 and relative risk 0.35; p=0.02, respectively). Overall survival at 3 years was 0.64 for the CB and 0.66 for the BM group. This study demonstrated the role of related donor CBT for malignant diseases in children [86]. Related donor CBT for non malignant diseases will be discussed in the non malignant section.

Comparison to bone marrow

No randomized trials had been conducted to compare CB with BM grafts. Few retrospective reports have been published. As for children, it was shown by Eapen that 503 cases of matched CBT had better 5 DFS than 116 matched unrelated donor (8/8) BMT. Even the 5/6 matched CBT had comparable results with the BM group. An important factor was the cell dose. The group that received more than 3x10⁷ nucleated cell/kg had better DFS and OS [28]. It was Rocha and Gluckman who assessed leukemia-free survival at 5 years after CBT or BMT in children. 503 children received CB – either matched or mismatched. The outcome of these transplantations was compared to BMT of 282 children. Allele-matched bone-marrow transplants had similar outcomes to transplants of umbilical cord blood mismatched for either one or two antigens. Higher survival rates were demonstrated after transplants of HLA-matched umbilical cord blood [87].

Recent publications have managed to evoke hopes that even in adults CBT (matched, or 1-2 HLA antigens mismatched) is as good as matched unrelated donor BMT. The reports of Laughlin, Rocha and Takahashi in late 2004 compared a large series of adult patients who received unrelated CB or BM. Outcomes of CBT were similar, and in certain aspects superior, to unrelated donor mismatched BMT. Laughlin found that patients receiving mismatched CB had similar treatment-related mortality, treatment failure, relapse and overall mortality rates, to those received mismatched BM. Rocha compared matched unrelated donor of BM with CB. He found no differences in treatment-related mortality rates, relapse and leukemia-free survival rates between them. These results may refine the accepted approach for unrelated donor search. Many believe that a search for a BM donor and a CB unit should generally be started simultaneously and CB (matched or mismatched in up to 2 HLA antigens) should be preferred if matched BM donor can not be found within a reasonable period of time [85, 51, 97]. In late 2006 Takahashi et al published the first report of adult transplantation with CB as a first option for non related donor graft. The Japanese group transplanted 100 adults with hematological malignancies with CB, if they had no matched related donor. Results of the CBT were compared to matched related BM or peripheral SC transplantations. The outcome was similar in all groups. Whether this interesting approach is feasible in all cases of patients with no matched related donor, relies upon further reports from other ethnic groups [98].

CBT for non malignant diseases

HSCT can offer the only true chance for cure in many non-malignant diseases. CB offers some unique advantages in the area of transplantations for non malignant diseases. Many of these patients are children. This makes nucleated cells doses satisfactory in most of the cases. Moreover, rareness of GVHD tempts the preference of CB, especially in an unrelated donor setup. As opposed to HSCT for malignant disease, there is no presumed benefit from the Graft Versus Leukemia effect of GVHD. On the other hand, CB is a less attractive option for transplantation for bone marrow failure syndromes. There are high rates of graft rejection in HSCT in these diseases. When adding the negative impact of CB's tendency for delayed engraftment, it is regarded by some as a problematic solution for such patients. This was demonstrated in the work of Rocha et al. In a related donor setting, and definitely with unrelated donors, for bone marrow failure syndrome patients, it was clear that engraftment, and therefore event free survival (EFS) rates are not acceptable. The probability of myeloid engraftment at day 60 was not more than 67% for patients that were given related donor grafts, and it was 36% in unrelated donor-CBT. Only 33% of the Fanconi anemia patients engrafted [1]. Better results were reported by the European group when they summarized unrelated CBT for Fanconi patients. Although only 12 of the 93 cases were HLA identical; 60% of the patients engrafted by day 60. A positive impact of Fludarabine based regimens, cell dose, and CMV negative recipients was seen [36].

Some limited experience was gained by us with a few bone marrow failure syndromes, namely Fanconi anemia. We observed high rates of event free survival (EFS), especially in children who received a matched family donor transplant [37].

In one case we used a novel strategy of pre-implantation genetic diagnosis for one of the patients. This method, which is based on CBT, could pave the way for many malignant and non-malignant diseases [11].

Although the role of HSCT for Thalassemia in the era of newer iron chelating agents is yet to be determined, this strategy is still being practiced widely in an attempt to cure this hemoglobinopathy. Locatelli et al reported results of related CBT in 44 children with hemoglobinopathies (Thalassemia and Sickle Cell Disease), and showed that this procedure is feasible. High rates of engraftment (89% at day 60) and EFS (79% for Thalassemia and 90% for Sickle Cell Disease) were achieved [61].

As for CBT in inborn errors of metabolism, Staba et al reported impressive results in children with Hurler syndrome who were given unrelated donors CB grafts. Even though 19 of the 20 patients received mismatched grafts, high rates of engraftment were reported (at 2.4 years follow-up, 85%). This was probably due to the relatively high nucleated cells doses (median of 10.5x10⁷ nucleated cells/kg). The disease itself was cured, as could be seen in all 17 patients who were alive, and had normal peripheral-blood α-L-Iduronidase activity [95]. Recently a report of a case of a child who was cured of Wolman disease by a CBT was published [96].

CBT for the cure of Sickle Cell Anemia was reported recently by a French group. Importantly the authors noticed that after a 6 year follow up the group of patients that received a CB graft did not develop the main contributing factor for the morbidity, GVHD [10].

Investigational approaches in cord blood

Most patients needing HSCT are adults. For these heavier patients CB is a problematic solution because of the relatively low cell dose. Various strategies are being attempted in order to lower the toxicity of the conditioning regimen. This could be achieved either by lowering its intensity, or by hastening engraftment.

Reduced intensity conditioning

The practice of HSCT with reduced intensity conditioning (RIC) has emerged in the adult population. These older patients usually have pre-existing morbidities.

By reducing the intensity of the preparative regimen it has been shown that treatment-related morbidity and mortality rates could be lowered. The concept behind this is based on the assumption that in certain cases the immunological impact of the graft is more important than the ablative power of the conditioning regimen.

Experience with transplantations using RIC, though follow up time is still short, have shown encouraging results. Patients who benefit the most from RIC are those with diseases of a more indolent nature.

Few studies of RIC-CBT in adult and pediatric patients have been published. The major conclusion that could be drawn from these series is that RIC is feasible in CBT. Graft rejection happened mainly in cases in which the accumulative chemotherapy dose experienced by the recipients prior to the transplantation itself was low. Though survival rates are low, it must be emphasized that most studies included mainly high risk, heavily treated patients. GVHD rates correlated with unrelated donor BMT. Another encouraging finding is the lower than expected rates of treatment-related mortality at 100 days post-transplantation. Because of the small number of patients, and diversity of methods, conclusions regarding the optimal RIC conditioning regimen, or the GVHD prophylaxis, can not be drawn at this point. Even if it is definitely too early to recruit patients for RIC-CBT outside clinical trials for selected patients, these protocols could offer an alternative for selected patients [69, 27, 19, 20, 13, 6, 4, 104].

Engraftment hastening

The idea of shortening the period from transplantation to myeloid recovery is at the basis of many strategies. Some have shown preliminary encouraging results in the laboratory, in animal models, and even in clinical trials.

Transplantations with double cord blood units

Many recipients receive more than one partially matched CB units where the cell dose in each is not sufficient. In many cases the sum of these units provides an adequate number of SC. It has been shown in animal models that two CB units provide high rates of engraftment [71]. Some studies have used this strategy for high risk adult patients who received two mismatched CB units. Many believe that this strategy could pave the way for lowering treatment-related mortality rates in CBT. In most of these trials two encouraging facts were observed: stable mixed chimerism, and no mutual rejection of mismatched units [7, 8, 25, 39, 5]. Brunstein et al have shown that by using a non-myeloablative regimen for CBT in adults, the OS of the group that received 2 units was higher than the patients who received 1 unit. In this study 92% of the patients achieved neutrophil recovery, at a median time of 12 days [16]. Interestingly, sustained hematopoiesis after double CBT is usually derived from a single donor. The relative percent viability, the infused number of NC and CD34⁺ cell doses, and the donor–recipient HLA-disparity are not helpful in predicting which of the two CB units will predominate. Although early data suggested that the dominant unit had a higher median infused CD3⁺ cell dose, this observation has not persisted with investigation of a larger cohort of patients. Order of infusion, location of HLA mismatch, ABO blood group and/or sex mismatch also did not have a predictive effect on engraftment.

Double CBT can potentially produce a better graft versus leukemia effect. This was demonstrated in a study of the University of Minnesota. They compared leukemia patients who received 2 units of CB to those who received a single unit. The group who received the double CBT had a lower risk for relapse. It is still not known if the relatively high degree of HLA mismatch in this setting is responsible. It might also be a consequence of non-HLA disparity, such as KIR mismatch, between the CB units and the recipient, or between themselves [100].

Double unit transplantation has become a major breakthrough in the field of CB during the last 2 years. Several 2 arms protocols for using double units are on their way. Whether these expectations are justified depends on preliminary results of these trials.

Co transplantation with a Haploidentical donor

Relaying on the assumption that almost every patient has a donor, namely a parent that has a similar HLA type of one of his haplotypes, Magro et al have succeeded in transplanting CB together with a Haploidentical graft. They succeeded in inducing a rapid engraftment via a BM transplant. By administering only a small dose of Haploidentical SC, the Spanish team managed to induce a temporary engraftment only. These cells were rejected later, due to their low dose and significant HLA disparity, allowing engraftment of the CB graft. 69% of these high risk patients survived at 4 years [65].

Intra-osseous transplantation

One of the obstacles to a short period of engraftment is the possibility that the homing process is influenced by anatomical barriers. It has been suggested that intra BM injection of the graft could induce a rapid engraftment. This has been shown to be feasible, and has improved engraftment kinetics in BMT in adults [41]. Time will tell if intra osseous transplantation could shorten the way for CB's SC into the BM, and therefore improve time to engraftment, as has been shown in animal models [103, 102]. 

Ex vivo expansion of hematopoietic stem cells

In vitro studies had shown that SC proliferate with the addition of cytokines. But uncontrolled expansion is not biologically satisfactory, since maturation and differentiation of SC occur in these conditions. The SC proliferate and become committed to specific hematopoietic cell lines. Such cells lack what is known as "long term population ability." The optimal composition of the cytokine-rich media of the ex vivo expansion process is an important challenge for researchers to face. It has been demonstrated by Shpall et al that co transplantation of ex vivo expanded and non-manipulated grafts are feasible. But in spite of this, improvements in engraftment kinetics, are yet to be achieved [15, 80, 47, 91, 92, 44, 75].

Different attitudes have been taken in order to refine the expansion process, namely: co-culturing with different cells as feeder layers [105, 21], selection of SC for the expansion [30], and multiplying the proliferative potential by performing a two step harvesting technique [66, 81]. None of these strategies have yet been introduced into clinical trials.

A somewhat more promising field is interference with the differentiation of expanded SC. Reports have been published recently regarding ex vivo expansion with copper chelator, Tetraethylenepentamine (TEPA), which enhances the long term populating ability of the CB cells. Following large scale experiments, this appealing approach has been introduced into the clinic in phase I trials. Preliminary encouraging results of this trial with no significant toxicity were presented recently [76-78, 40, 93]. A Phase II multi center study has just started and the first 3 adult patients with hematological malignancies have already been recruited [26]. The same concept was behind the experiment held by Nolta et al, when they co-cultured primitive CB's SC (CD34⁺ CD38^-) together with a feeder layer of immortalized murine stromal cell-line AFT024. This method has yielded high rates of myeloid and lymphoid engraftment in a NOD/SCID mouse xenograft model [74]. Other molecules that play major roles in the differentiation of hematopoietic cells, and might be used in the future for ex vivo expansion of CB are Gfi-1 and some of the Notch ligand protein family [52, 53, 42]. Novel methods have been studied recently with the use of epigenetic factors. Silencing of genes could be a consequence of methylation of their promoters or deacetylation of histones. By trying to inhibit these processes, reactivation of some genes could augment the hematopoietic SC's self renewal potential. Recent publications have shown some success in the in vitro repopulating potential of CB when using histone deacetylase inhibitors, such as Valproic acid [7, 24]. This strategy is  the basis of a clinical study which has recruited the first patients (personal communications).

Cord Blood, Umbilical cord, and Mesenchymal Stem Cells

As their unique qualities are revealed, the interest in mesenchymal stem cells (MSCs) is growing continuously. These cells are non-hematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues, but possibly also to other tissue lineages. They have an in vitro expansion ability while their growth and differentiation potential is maintained. Currently it is expected that they could be used for tissue repair and regenerative medicine. MSCs have shown that they can modulate immune response both in vitro and in vivo. Preliminary studies are on their way for using MSCs as an anti GVHD prophylaxis. It was doubted that these cells could also play a roll in treating GVHD. It has also been postulated that these cells could be used for other immune mediated diseases. MSCs are used as a growing medium for ex vivo expansion of other cells [67, 84]. Le Blanc et al showed that MSCs could be transfused in parallel to HSC grafts and demonstrated fast engraftment [54]. Finally, MSCs are considered to be candidates as a vector for gene therapy.

Until recently only BM and adipose tissue were considered as a source for MSC. In the last few years it had been shown that CB contains MSC [55]. MSC from other sources has been demonstrated to have suppressive effect on T cells [58]. Few studies have focused on the different properties of MSC originating from CB. Their tendency to differentiate into specific tissue, their genomic expression, and proliferative response, are all different from BM or adipose tissue MSC [18, 46].

When considering the expulsion of the placenta at the end of delivery as a waste of a precious source of SCs, it is not only the CB itself that should be regarded as such. The Wharton jelly in the umbilical cord has also been found to be a source for MSCs [31, 90].

Cord blood uses in other fields

Gene transfer is an exciting new field in which CB could serve as a vector for correcting inborn genetic errors, or replace infected hematopoietic SC, such as in the case of HIV. Its availability, proliferative response, and engraftment potential, make it an appealing candidate for these uses [43]. Clinical trials of gene transfer to Adenosine Deaminase deficient Severe Combined Immunodeficiency children relied on BM and CB as a hematopoietic SC source. This method faced some obstacles that continue to prevent it from curing these patients [48, 2].

Another – to date only investigational – field is the potential non-hematopoietic use of hematopoietic SC. In recent years much interest has been focused on the ability of hematopoietic SC to differentiate into (or as some claim, to fuse with) cells of other tissues. It was demonstrated that cells with pluripotent differentiation potential could be found in CB [79, 72, 38]. CB has been suggested to have a role in improving performance of rats who were subjected to brain infarct [99]. CB is also considered by some to be a source of SC for regeneration of ischemic heart tissue by differentiation processes or neoangiogenesis [63]. It is too early to define whether SC's plasticity might have clinical benefits in repairing injured tissues, but this application is at the center of great interest and controversy.

Discussion

CB has become a legitimate source, not only for HSC for transplantations, but also for other uses. The experience gained in the last twenty years of work with CBT has shown us its advantages, as well as its setbacks.

Unlike BM donations, CB's collection is easier and poses no danger to the donor. In CB banks there is a greater proportion of ethnic minorities than in BM registries. It also has greater availability in an unrelated donor HSCT due to its shorter donor search time. Lesser risk for transmission of infectious agents in the transplantation process is another benefit of CB. There is no doubt that fewer HLA restrictions in unrelated transplantations is its main advantage. This fact allows successful transplantations with acceptable rates of graft failure and GVHD.

On the other hand, there is a slim potential for disease transmission, namely genetic, in CBT setup. In CBT there is almost no option for a second transplantation, or any boost of cells. A troubling disadvantage of CB is its low number of hematopoietic SC in each unit. This has proven to be a crucial point that has a direct relationship to relatively high rates of treatment-related mortality rates in CBT. This point is further emphasized within the setting of adult transplantations.

From the data collected in several series of CBT for both malignant and non malignant diseases it appears that CB can be used as a SC source in several settings.

The most urgent need for SC is transplantation for malignant diseases from unrelated donors. It is an acceptable approach to search first for BM donor. If a 5/6 or better HLA match can not be found, or progressive disease status does not allow completion of the search, then a CBT of 4/6 HLA match or better should be performed. This of course depends on a minimal cell dose of 2x10⁷ nucleated cells/kg per CB unit. Cell dose has greater relevancy in adult transplantation setup. Skepticism about the possibility of CBT in heavier patients might fade as newer strategies could overcome SC scarceness of nucleated cells in CB. At this stage the most appealing strategy is the double unit CBT. By receiving 2 CB units many adults could be transplanted with a reasonable time to engraftment. Time will tell if other methods could offer a solution for a better outcome in CBT for adults.

Impressive progress is constantly being achieved in the field of CBT. CB is still considered a second best choice for HSCT, but as newer reports are being published it is not so obvious whether it could not be preferred over BM. Interesting data in children showed that a perfect match (6/6) of CB could be the best choice. If larger studies can confirm this, we might see CB becoming the first option for transplantation in certain conditions.

For non malignant disease CB is a very good option, especially for the smaller patients. Caution should be practiced when using CB for bone marrow failure syndrome, though again it seems that larger units and better preparative regimens may overcome the tendency for graft failure.

Future uses of CB may not be just for HSCT. Time will tell if the fields of gene therapy and non hematopoietic injured tissues repair also benefit from the use of CB cells.

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Introduction

The birth of every newborn human produces a precious byproduct. In the expelled placenta there is a sufficient amount of Cord Blood (CB), in which there is abundance of hematopoietic elements. In 1988 Elaine Gluckman showed that a Hematopoietic Stem Cell Transplantation (HSCT) can succeed by using CB as a source for the graft [33]. Gradually thousands of such transplantations began to be performed all over the world. Up until recently most transplantations with CB had been done in children; however the main progress in the field in the last 2 years has been achieved in adults with hematological malignancies. But even though HSCT is still the major indication for using CB, there is a growing interest in finding it as a source for non-hematopoietic stem cells (SC) for regenerative medicine, gene therapy vector, and other potential uses.

Collection of cord blood in the delivery room

CB's collection is done in the delivery room. The blood is drawn from the umbilical vein, before or after the expulsion of the placenta.

The main advantage of the collection process of CB is its simplicity. It poses no danger and causes no pain to the laboring mother or the newborn. Before the collection itself consent is given by the mother. Some centers also addend a short interview, and others use questionnaires for identification of high risk mothers [29].

Cryopreservation

After its collection CB undergoes cryopreservation. The most widely used method is the one reported by Rubinstein et al [89]. It is based on red blood cell depletion and volume reduction. At the end of the process the total volume of each unit is 25 milliliters.

Cord blood public banks

Before freezing, CB samples undergo several tests. Every unit is screened for infectious agents, and in some banks, for relevant inherited diseases. HLA typing is usually done for A, B in serology, and DR in DNA. Some diversity exists between banks with regard to the routine tests that each unit undergoes. Additional samples are maintained in small plastic segments attached to the frozen unit in case future tests are needed.

It is estimated that today there are about 250,000 CB units frozen in 35 banks in 21 countries [14]. CB banking is facing some challenges. The first is the scarcity of space, which is dealt with by volume reduction methods and selection of presumed optimal units, usually with higher volume. Another issue is the uncertainty regarding the period of time which units can be preserved without damage to the viability of the cells. The banks also face ethical issues. For example, if an adult disagrees with the usage of CB that his parents gave consent for donation for decades ago, what is the value of such consent? Another concern is the fate of the information that is stored in CB banks regarding donors' infectious status or the presence of genetic diseases. Is this sensitive data protected as it should be? The need for follow up is understandable, but it could also affect the diversity of ethnic pool of the donors. The ability to detect the donors might also put their families under pressure to donate more cells when the need for it might come.

The importance of public CB banking gained an official acknowledgment when the American congress decided to add $30 million for collection of an additional 150,000 units.

Apart from the above, one of the most controversial issues is private CB banking.

Private cord blood banks

This is an ever growing trend that emerged in the early 90s. These private firms offer storage of CB units against a future need for autologous or related allogeneic transplantations. Questions have been recently being raised  about whether overanxious parents are truly aware that there are no indications today for autologous cord blood transplantation (CBT). Are they informed about the slim chances for a family of ever needing a sibling CBT, and do they know about the lack of knowledge regarding the how long CB's hematopoietic SC preserve their viability while frozen?

The pace of collection in the private banks exceeds the one in the public banks. It is estimated that approximately 600,000 units are frozen privately. These facts raise questions about whether this limited source of hematopoietic SC should not be solely in public hands.

The unique properties of cord blood

Aspirates of bone marrow (BM), or the more recently used Peripheral Blood Stem Cell Collection (PBSC) product, have been traditionally used as sources for HSCT. CB has a few different qualities.

It had long been acknowledged that the more nucleated cells in a graft, the better the chances of engraftment. When taking CB into account as a hematopoietic SC source for transplantation, it is evident that it has fewer nucleated cells than other sources. Each aspirate of BM yields 750-1000 milliliters. This volume usually gives a nucleated cell dose of 2x10⁸/kg for an average weight adult. The product of PBSC yields similar number of SC. The volume of a typical CB unit is usually only 75-150 milliliters. The nucleated cells dose is only one tenth of the BM dose, usually no more than 2x10⁷/kg, for an adult.

Another relevant component of the graft that marks the difference between CB and BM is T cells. These are considered to have a deleterious effect regarding the immune response of the graft against the recipient. The total dose of T cells (CD3⁺ cells) in CB units is less than a fifth of the amount in BM grafts. When comparing it to mobilized peripheral blood grafts, CB units have less than 2% of T cell dose. But while less hematopoietic SC in CB is a setback regarding HSCT, the scarceness of T cells is an advantage, with respect to the risk of graft versus host disease (GVHD) [9, 12].

The low number of SC in CB graft is masked by an excellent proliferative response. When these cells are in a dormant state and cytokines are introduced into their environment, they expand much better than hematopoietic SC of BM. This trait enables CB to produce full hematopoietic recovery of BM in myeloablated recipients [64, 57].

The naïve nature of the immune system's cells in CB is a different issue.

The lymphocytes in CB grafts have a more tolerant nature [73, 82, 83, 88, 22, 32]. Other components of the system, such as dendritic and Natural Killer cells also have different properties, when compared to BM or adult peripheral blood [56, 45, 94, 17, 59, 23]. Because of this, CB allows greater human leukocyte antigen (HLA) disparities in transplantations, with less rejection and lower rates of GVHD.

Cord blood transplantation, clinical experience

Reports on a series of CBT started to appear at the beginning of the end of the 1990s and at the beginning of the third millennium. These were based mostly on the American and the European registries, with some reports from Japanese and other institutes. Table 1 & 2 summarizes the largest clinical trials of CBT using unrelated donors [89, 34, 101, 68, 60, 49, 50, 85, 97, 62]. A few important concepts could be built upon results from these works. First was the notion that CB, with its limited nucleated cells dose, can produce full hematopoietic reconstitution after myeloablative conditioning. Secondly, the median time of myeloid recovery in CBT ranged from 22 to 33 days. This is a far longer period than the time in bone marrow transplantation (BMT) experience. When BM aplasia is prolonged, morbidity and mortality rates rise. The third notion was that despite the existence of a significant proportion of HLA disparity between donors and recipients, rejection and GVHD rates were surprisingly low.

So these trials proved that CB is a legitimate source for HSCT, with problematic engraftment kinetics, but less restriction to HLA matching when compared to BM.

Since each placenta contains a limited volume of blood, it follows that there is also a limited amount of nucleated cells per unit. The correlation between nucleated cell dose and transplantation outcomes was evaluated. A positive impact of cell dose on time to engraftment, and hence the overall survival, has been demonstrated in both pediatric and adult series. It is probably agreed that the minimal acceptable threshold of nucleated cells dose should be 1.5x10⁷ nucleated cells/kg, but an association between dose of 3.7x10⁷ nucleated cells/kg and more and faster time to neutrophil engraftment was suggested by the Eurocord [34, 3]. The New York Blood Group reported that 2.5x10⁷ nucleated cells/kg is the minimal threshold for transplantation [89].

Historically CD34⁺ cells counts were not part of the tests done routinely on CB units. But it is reasonable to assume that it might be so in the near future. Counting nucleated cells involves many cells that do not contribute to the engraftment potential. And indeed, Wagner et al has shown a correlation between CD34⁺ dose of 1.7x10⁵cell/kg and higher to rapid neutrophil engraftment and probability of engraftment [101].

Related donor transplants

Although the first CBT was done from a sibling donor, related donors transplants are used less frequently in this setup. For the cure of malignant diseases CB from a sibling could be used if there is a perfect timing of a birth in the family, or a if a CB unit had been cryopreserved earlier, either by chance or by intention. In non-malignant disease there is usually more time. Families that are aware of CB as a source for transplantation might act on time when births are due.

Several reports of large series of trials have been published. These series have demonstrated that CB is a valid therapeutic option as a source for pediatric transplantation for malignant and non-malignant diseases. The probability for survival at 1 year was 0.63 (95% CI: 0.57-0.69) in the Eurocord study, and 0.61 (95% CI: 0.81-0.49) at 2 years in the ICBTR study [89, 35].

The largest of the series is a joint European and American work that compared 113 related donor CBT in children with 2052 cases of related donor BMT. Neutrophils engraftment in the CB group occurred at a median time of 26 days, compared to 18 in the BM group. Probability of myeloid recovery at day 60 was 0.89 and 0.98 in the CB and BM respectively. Children who received CB had a significantly lower risk of both AGVHD and CGVHD than those who were transplanted from BM (relative risk 0.41; p=0.001 and relative risk 0.35; p=0.02, respectively). Overall survival at 3 years was 0.64 for the CB and 0.66 for the BM group. This study demonstrated the role of related donor CBT for malignant diseases in children [86]. Related donor CBT for non malignant diseases will be discussed in the non malignant section.

Comparison to bone marrow

No randomized trials had been conducted to compare CB with BM grafts. Few retrospective reports have been published. As for children, it was shown by Eapen that 503 cases of matched CBT had better 5 DFS than 116 matched unrelated donor (8/8) BMT. Even the 5/6 matched CBT had comparable results with the BM group. An important factor was the cell dose. The group that received more than 3x10⁷ nucleated cell/kg had better DFS and OS [28]. It was Rocha and Gluckman who assessed leukemia-free survival at 5 years after CBT or BMT in children. 503 children received CB – either matched or mismatched. The outcome of these transplantations was compared to BMT of 282 children. Allele-matched bone-marrow transplants had similar outcomes to transplants of umbilical cord blood mismatched for either one or two antigens. Higher survival rates were demonstrated after transplants of HLA-matched umbilical cord blood [87].

Recent publications have managed to evoke hopes that even in adults CBT (matched, or 1-2 HLA antigens mismatched) is as good as matched unrelated donor BMT. The reports of Laughlin, Rocha and Takahashi in late 2004 compared a large series of adult patients who received unrelated CB or BM. Outcomes of CBT were similar, and in certain aspects superior, to unrelated donor mismatched BMT. Laughlin found that patients receiving mismatched CB had similar treatment-related mortality, treatment failure, relapse and overall mortality rates, to those received mismatched BM. Rocha compared matched unrelated donor of BM with CB. He found no differences in treatment-related mortality rates, relapse and leukemia-free survival rates between them. These results may refine the accepted approach for unrelated donor search. Many believe that a search for a BM donor and a CB unit should generally be started simultaneously and CB (matched or mismatched in up to 2 HLA antigens) should be preferred if matched BM donor can not be found within a reasonable period of time [85, 51, 97]. In late 2006 Takahashi et al published the first report of adult transplantation with CB as a first option for non related donor graft. The Japanese group transplanted 100 adults with hematological malignancies with CB, if they had no matched related donor. Results of the CBT were compared to matched related BM or peripheral SC transplantations. The outcome was similar in all groups. Whether this interesting approach is feasible in all cases of patients with no matched related donor, relies upon further reports from other ethnic groups [98].

CBT for non malignant diseases

HSCT can offer the only true chance for cure in many non-malignant diseases. CB offers some unique advantages in the area of transplantations for non malignant diseases. Many of these patients are children. This makes nucleated cells doses satisfactory in most of the cases. Moreover, rareness of GVHD tempts the preference of CB, especially in an unrelated donor setup. As opposed to HSCT for malignant disease, there is no presumed benefit from the Graft Versus Leukemia effect of GVHD. On the other hand, CB is a less attractive option for transplantation for bone marrow failure syndromes. There are high rates of graft rejection in HSCT in these diseases. When adding the negative impact of CB's tendency for delayed engraftment, it is regarded by some as a problematic solution for such patients. This was demonstrated in the work of Rocha et al. In a related donor setting, and definitely with unrelated donors, for bone marrow failure syndrome patients, it was clear that engraftment, and therefore event free survival (EFS) rates are not acceptable. The probability of myeloid engraftment at day 60 was not more than 67% for patients that were given related donor grafts, and it was 36% in unrelated donor-CBT. Only 33% of the Fanconi anemia patients engrafted [1]. Better results were reported by the European group when they summarized unrelated CBT for Fanconi patients. Although only 12 of the 93 cases were HLA identical; 60% of the patients engrafted by day 60. A positive impact of Fludarabine based regimens, cell dose, and CMV negative recipients was seen [36].

Some limited experience was gained by us with a few bone marrow failure syndromes, namely Fanconi anemia. We observed high rates of event free survival (EFS), especially in children who received a matched family donor transplant [37].

In one case we used a novel strategy of pre-implantation genetic diagnosis for one of the patients. This method, which is based on CBT, could pave the way for many malignant and non-malignant diseases [11].

Although the role of HSCT for Thalassemia in the era of newer iron chelating agents is yet to be determined, this strategy is still being practiced widely in an attempt to cure this hemoglobinopathy. Locatelli et al reported results of related CBT in 44 children with hemoglobinopathies (Thalassemia and Sickle Cell Disease), and showed that this procedure is feasible. High rates of engraftment (89% at day 60) and EFS (79% for Thalassemia and 90% for Sickle Cell Disease) were achieved [61].

As for CBT in inborn errors of metabolism, Staba et al reported impressive results in children with Hurler syndrome who were given unrelated donors CB grafts. Even though 19 of the 20 patients received mismatched grafts, high rates of engraftment were reported (at 2.4 years follow-up, 85%). This was probably due to the relatively high nucleated cells doses (median of 10.5x10⁷ nucleated cells/kg). The disease itself was cured, as could be seen in all 17 patients who were alive, and had normal peripheral-blood α-L-Iduronidase activity [95]. Recently a report of a case of a child who was cured of Wolman disease by a CBT was published [96].

CBT for the cure of Sickle Cell Anemia was reported recently by a French group. Importantly the authors noticed that after a 6 year follow up the group of patients that received a CB graft did not develop the main contributing factor for the morbidity, GVHD [10].

Investigational approaches in cord blood

Most patients needing HSCT are adults. For these heavier patients CB is a problematic solution because of the relatively low cell dose. Various strategies are being attempted in order to lower the toxicity of the conditioning regimen. This could be achieved either by lowering its intensity, or by hastening engraftment.

Reduced intensity conditioning

The practice of HSCT with reduced intensity conditioning (RIC) has emerged in the adult population. These older patients usually have pre-existing morbidities.

By reducing the intensity of the preparative regimen it has been shown that treatment-related morbidity and mortality rates could be lowered. The concept behind this is based on the assumption that in certain cases the immunological impact of the graft is more important than the ablative power of the conditioning regimen.

Experience with transplantations using RIC, though follow up time is still short, have shown encouraging results. Patients who benefit the most from RIC are those with diseases of a more indolent nature.

Few studies of RIC-CBT in adult and pediatric patients have been published. The major conclusion that could be drawn from these series is that RIC is feasible in CBT. Graft rejection happened mainly in cases in which the accumulative chemotherapy dose experienced by the recipients prior to the transplantation itself was low. Though survival rates are low, it must be emphasized that most studies included mainly high risk, heavily treated patients. GVHD rates correlated with unrelated donor BMT. Another encouraging finding is the lower than expected rates of treatment-related mortality at 100 days post-transplantation. Because of the small number of patients, and diversity of methods, conclusions regarding the optimal RIC conditioning regimen, or the GVHD prophylaxis, can not be drawn at this point. Even if it is definitely too early to recruit patients for RIC-CBT outside clinical trials for selected patients, these protocols could offer an alternative for selected patients [69, 27, 19, 20, 13, 6, 4, 104].

Engraftment hastening

The idea of shortening the period from transplantation to myeloid recovery is at the basis of many strategies. Some have shown preliminary encouraging results in the laboratory, in animal models, and even in clinical trials.

Transplantations with double cord blood units

Many recipients receive more than one partially matched CB units where the cell dose in each is not sufficient. In many cases the sum of these units provides an adequate number of SC. It has been shown in animal models that two CB units provide high rates of engraftment [71]. Some studies have used this strategy for high risk adult patients who received two mismatched CB units. Many believe that this strategy could pave the way for lowering treatment-related mortality rates in CBT. In most of these trials two encouraging facts were observed: stable mixed chimerism, and no mutual rejection of mismatched units [7, 8, 25, 39, 5]. Brunstein et al have shown that by using a non-myeloablative regimen for CBT in adults, the OS of the group that received 2 units was higher than the patients who received 1 unit. In this study 92% of the patients achieved neutrophil recovery, at a median time of 12 days [16]. Interestingly, sustained hematopoiesis after double CBT is usually derived from a single donor. The relative percent viability, the infused number of NC and CD34⁺ cell doses, and the donor–recipient HLA-disparity are not helpful in predicting which of the two CB units will predominate. Although early data suggested that the dominant unit had a higher median infused CD3⁺ cell dose, this observation has not persisted with investigation of a larger cohort of patients. Order of infusion, location of HLA mismatch, ABO blood group and/or sex mismatch also did not have a predictive effect on engraftment.

Double CBT can potentially produce a better graft versus leukemia effect. This was demonstrated in a study of the University of Minnesota. They compared leukemia patients who received 2 units of CB to those who received a single unit. The group who received the double CBT had a lower risk for relapse. It is still not known if the relatively high degree of HLA mismatch in this setting is responsible. It might also be a consequence of non-HLA disparity, such as KIR mismatch, between the CB units and the recipient, or between themselves [100].

Double unit transplantation has become a major breakthrough in the field of CB during the last 2 years. Several 2 arms protocols for using double units are on their way. Whether these expectations are justified depends on preliminary results of these trials.

Co transplantation with a Haploidentical donor

Relaying on the assumption that almost every patient has a donor, namely a parent that has a similar HLA type of one of his haplotypes, Magro et al have succeeded in transplanting CB together with a Haploidentical graft. They succeeded in inducing a rapid engraftment via a BM transplant. By administering only a small dose of Haploidentical SC, the Spanish team managed to induce a temporary engraftment only. These cells were rejected later, due to their low dose and significant HLA disparity, allowing engraftment of the CB graft. 69% of these high risk patients survived at 4 years [65].

Intra-osseous transplantation

One of the obstacles to a short period of engraftment is the possibility that the homing process is influenced by anatomical barriers. It has been suggested that intra BM injection of the graft could induce a rapid engraftment. This has been shown to be feasible, and has improved engraftment kinetics in BMT in adults [41]. Time will tell if intra osseous transplantation could shorten the way for CB's SC into the BM, and therefore improve time to engraftment, as has been shown in animal models [103, 102]. 

Ex vivo expansion of hematopoietic stem cells

In vitro studies had shown that SC proliferate with the addition of cytokines. But uncontrolled expansion is not biologically satisfactory, since maturation and differentiation of SC occur in these conditions. The SC proliferate and become committed to specific hematopoietic cell lines. Such cells lack what is known as "long term population ability." The optimal composition of the cytokine-rich media of the ex vivo expansion process is an important challenge for researchers to face. It has been demonstrated by Shpall et al that co transplantation of ex vivo expanded and non-manipulated grafts are feasible. But in spite of this, improvements in engraftment kinetics, are yet to be achieved [15, 80, 47, 91, 92, 44, 75].

Different attitudes have been taken in order to refine the expansion process, namely: co-culturing with different cells as feeder layers [105, 21], selection of SC for the expansion [30], and multiplying the proliferative potential by performing a two step harvesting technique [66, 81]. None of these strategies have yet been introduced into clinical trials.

A somewhat more promising field is interference with the differentiation of expanded SC. Reports have been published recently regarding ex vivo expansion with copper chelator, Tetraethylenepentamine (TEPA), which enhances the long term populating ability of the CB cells. Following large scale experiments, this appealing approach has been introduced into the clinic in phase I trials. Preliminary encouraging results of this trial with no significant toxicity were presented recently [76-78, 40, 93]. A Phase II multi center study has just started and the first 3 adult patients with hematological malignancies have already been recruited [26]. The same concept was behind the experiment held by Nolta et al, when they co-cultured primitive CB's SC (CD34⁺ CD38^-) together with a feeder layer of immortalized murine stromal cell-line AFT024. This method has yielded high rates of myeloid and lymphoid engraftment in a NOD/SCID mouse xenograft model [74]. Other molecules that play major roles in the differentiation of hematopoietic cells, and might be used in the future for ex vivo expansion of CB are Gfi-1 and some of the Notch ligand protein family [52, 53, 42]. Novel methods have been studied recently with the use of epigenetic factors. Silencing of genes could be a consequence of methylation of their promoters or deacetylation of histones. By trying to inhibit these processes, reactivation of some genes could augment the hematopoietic SC's self renewal potential. Recent publications have shown some success in the in vitro repopulating potential of CB when using histone deacetylase inhibitors, such as Valproic acid [7, 24]. This strategy is  the basis of a clinical study which has recruited the first patients (personal communications).

Cord Blood, Umbilical cord, and Mesenchymal Stem Cells

As their unique qualities are revealed, the interest in mesenchymal stem cells (MSCs) is growing continuously. These cells are non-hematopoietic stromal cells that are capable of differentiating into, and contribute to the regeneration of, mesenchymal tissues, but possibly also to other tissue lineages. They have an in vitro expansion ability while their growth and differentiation potential is maintained. Currently it is expected that they could be used for tissue repair and regenerative medicine. MSCs have shown that they can modulate immune response both in vitro and in vivo. Preliminary studies are on their way for using MSCs as an anti GVHD prophylaxis. It was doubted that these cells could also play a roll in treating GVHD. It has also been postulated that these cells could be used for other immune mediated diseases. MSCs are used as a growing medium for ex vivo expansion of other cells [67, 84]. Le Blanc et al showed that MSCs could be transfused in parallel to HSC grafts and demonstrated fast engraftment [54]. Finally, MSCs are considered to be candidates as a vector for gene therapy.

Until recently only BM and adipose tissue were considered as a source for MSC. In the last few years it had been shown that CB contains MSC [55]. MSC from other sources has been demonstrated to have suppressive effect on T cells [58]. Few studies have focused on the different properties of MSC originating from CB. Their tendency to differentiate into specific tissue, their genomic expression, and proliferative response, are all different from BM or adipose tissue MSC [18, 46].

When considering the expulsion of the placenta at the end of delivery as a waste of a precious source of SCs, it is not only the CB itself that should be regarded as such. The Wharton jelly in the umbilical cord has also been found to be a source for MSCs [31, 90].

Cord blood uses in other fields

Gene transfer is an exciting new field in which CB could serve as a vector for correcting inborn genetic errors, or replace infected hematopoietic SC, such as in the case of HIV. Its availability, proliferative response, and engraftment potential, make it an appealing candidate for these uses [43]. Clinical trials of gene transfer to Adenosine Deaminase deficient Severe Combined Immunodeficiency children relied on BM and CB as a hematopoietic SC source. This method faced some obstacles that continue to prevent it from curing these patients [48, 2].

Another – to date only investigational – field is the potential non-hematopoietic use of hematopoietic SC. In recent years much interest has been focused on the ability of hematopoietic SC to differentiate into (or as some claim, to fuse with) cells of other tissues. It was demonstrated that cells with pluripotent differentiation potential could be found in CB [79, 72, 38]. CB has been suggested to have a role in improving performance of rats who were subjected to brain infarct [99]. CB is also considered by some to be a source of SC for regeneration of ischemic heart tissue by differentiation processes or neoangiogenesis [63]. It is too early to define whether SC's plasticity might have clinical benefits in repairing injured tissues, but this application is at the center of great interest and controversy.

Discussion

CB has become a legitimate source, not only for HSC for transplantations, but also for other uses. The experience gained in the last twenty years of work with CBT has shown us its advantages, as well as its setbacks.

Unlike BM donations, CB's collection is easier and poses no danger to the donor. In CB banks there is a greater proportion of ethnic minorities than in BM registries. It also has greater availability in an unrelated donor HSCT due to its shorter donor search time. Lesser risk for transmission of infectious agents in the transplantation process is another benefit of CB. There is no doubt that fewer HLA restrictions in unrelated transplantations is its main advantage. This fact allows successful transplantations with acceptable rates of graft failure and GVHD.

On the other hand, there is a slim potential for disease transmission, namely genetic, in CBT setup. In CBT there is almost no option for a second transplantation, or any boost of cells. A troubling disadvantage of CB is its low number of hematopoietic SC in each unit. This has proven to be a crucial point that has a direct relationship to relatively high rates of treatment-related mortality rates in CBT. This point is further emphasized within the setting of adult transplantations.

From the data collected in several series of CBT for both malignant and non malignant diseases it appears that CB can be used as a SC source in several settings.

The most urgent need for SC is transplantation for malignant diseases from unrelated donors. It is an acceptable approach to search first for BM donor. If a 5/6 or better HLA match can not be found, or progressive disease status does not allow completion of the search, then a CBT of 4/6 HLA match or better should be performed. This of course depends on a minimal cell dose of 2x10⁷ nucleated cells/kg per CB unit. Cell dose has greater relevancy in adult transplantation setup. Skepticism about the possibility of CBT in heavier patients might fade as newer strategies could overcome SC scarceness of nucleated cells in CB. At this stage the most appealing strategy is the double unit CBT. By receiving 2 CB units many adults could be transplanted with a reasonable time to engraftment. Time will tell if other methods could offer a solution for a better outcome in CBT for adults.

Impressive progress is constantly being achieved in the field of CBT. CB is still considered a second best choice for HSCT, but as newer reports are being published it is not so obvious whether it could not be preferred over BM. Interesting data in children showed that a perfect match (6/6) of CB could be the best choice. If larger studies can confirm this, we might see CB becoming the first option for transplantation in certain conditions.

For non malignant disease CB is a very good option, especially for the smaller patients. Caution should be practiced when using CB for bone marrow failure syndrome, though again it seems that larger units and better preparative regimens may overcome the tendency for graft failure.

Future uses of CB may not be just for HSCT. Time will tell if the fields of gene therapy and non hematopoietic injured tissues repair also benefit from the use of CB cells.

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Гэл Гольдштейн, Амос Торен, Арнон Наглер

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10538" ["VALUE"]=> array(2) { ["TEXT"]=> string(4975) "<p class="bodytext">Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных. </p> <p class="bodytext">Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга. </p> <p class="bodytext">Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4909) "

Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных.

Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга.

Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).

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Gal Goldstein¹, Amos Toren¹, Arnon Nagler²

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¹Pediatric Hemato-Oncology Department, The Edmond and Lily Safra children's Hospital;
²Division of Hematology and Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer and Sackler school of Medicine, Tel Aviv University, Tel Aviv, Israel

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The review article concerns the transplantation of hematopoietic stem cells (HSCs) derived from cord blood (CB). This approach was previously used in pediatric settings. In partu procedures of CB HSCs harvesting, along with the routine methods of their quality control (i.e., HLA typing, testing for infectious pathogens) are listed in brief. Ca. 250,000 CB units are now stored in 35 blood banks in 21 countries worldwide. Some ethical problems with application of CB cells could arise during their long-term storage. The authors point to the controversies associated with the development of private cord blood banks (capacity is estimated at 600,000 CB units), due to indefinite and/or indefensible terms of their storage for eventual transplants. The specific potential of CB HSCs is limited by small sample volume; however relatively low numbers of HSCs with high proliferative activities, along with lower counts of T lymphocytes and their higher immunological tolerance enable HSC transplants at reduced rejection risk and lower GvHD rates.

Clinical experience with CB HSC transplantation is compared for different centers, where the high efficiency of this approach is shown, being, however, associated with longer terms of hematopoietic recovery when compared to bone marrow transplants. A minimal acceptable HSC CB dose is estimated as 1.5-2.5x10⁷ nucleated cells per kg body mass of a patient. The main areas of CB HSC transplantation are described, i.e., related or unrelated transplants, performed in non-cancer and malignant disorders. The authors point to scarce data comparing the efficiency of HSCs derived from cord blood versus bone marrow samples.

Special attention is paid to CB HSC transplantation in non-malignant conditions with bone marrow aplasia associated with unacceptably high non-engraftment risk. Good results of CB HSCT are demonstrated in hemoglobinopathies and mucopolysaccharidoses. When administering CB HSCs to adult patients, non-myeloablative conditioning regimens are proposed, despite the poorly defined efficiency of such an approach. An opportunity for simultaneous transplants of two or more HSC units is considered, including a unit of CB HSCs. An option of intraosseous CB HSC injection is also discussed. In vitro techniques of CB HSC expansion are under development, in spite of scarce data on their proliferative rates and differentiation ability. As an additional stimulus, injection of mesenchymal stem cells together with CB HSCs was recently proposed. In conclusion, the possible usage of normal CB HSCs to correct genetic deficiencies in children is described. CB HSCs' pluripotency may be also applied to the repair of various tissue lesions, e.g., myocardial infarction, or vascular defects.

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Gal Goldstein¹, Amos Toren¹, Arnon Nagler²

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Gal Goldstein¹, Amos Toren¹, Arnon Nagler²

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The review article concerns the transplantation of hematopoietic stem cells (HSCs) derived from cord blood (CB). This approach was previously used in pediatric settings. In partu procedures of CB HSCs harvesting, along with the routine methods of their quality control (i.e., HLA typing, testing for infectious pathogens) are listed in brief. Ca. 250,000 CB units are now stored in 35 blood banks in 21 countries worldwide. Some ethical problems with application of CB cells could arise during their long-term storage. The authors point to the controversies associated with the development of private cord blood banks (capacity is estimated at 600,000 CB units), due to indefinite and/or indefensible terms of their storage for eventual transplants. The specific potential of CB HSCs is limited by small sample volume; however relatively low numbers of HSCs with high proliferative activities, along with lower counts of T lymphocytes and their higher immunological tolerance enable HSC transplants at reduced rejection risk and lower GvHD rates.

Clinical experience with CB HSC transplantation is compared for different centers, where the high efficiency of this approach is shown, being, however, associated with longer terms of hematopoietic recovery when compared to bone marrow transplants. A minimal acceptable HSC CB dose is estimated as 1.5-2.5x10⁷ nucleated cells per kg body mass of a patient. The main areas of CB HSC transplantation are described, i.e., related or unrelated transplants, performed in non-cancer and malignant disorders. The authors point to scarce data comparing the efficiency of HSCs derived from cord blood versus bone marrow samples.

Special attention is paid to CB HSC transplantation in non-malignant conditions with bone marrow aplasia associated with unacceptably high non-engraftment risk. Good results of CB HSCT are demonstrated in hemoglobinopathies and mucopolysaccharidoses. When administering CB HSCs to adult patients, non-myeloablative conditioning regimens are proposed, despite the poorly defined efficiency of such an approach. An opportunity for simultaneous transplants of two or more HSC units is considered, including a unit of CB HSCs. An option of intraosseous CB HSC injection is also discussed. In vitro techniques of CB HSC expansion are under development, in spite of scarce data on their proliferative rates and differentiation ability. As an additional stimulus, injection of mesenchymal stem cells together with CB HSCs was recently proposed. In conclusion, the possible usage of normal CB HSCs to correct genetic deficiencies in children is described. CB HSCs' pluripotency may be also applied to the repair of various tissue lesions, e.g., myocardial infarction, or vascular defects.

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The review article concerns the transplantation of hematopoietic stem cells (HSCs) derived from cord blood (CB). This approach was previously used in pediatric settings. In partu procedures of CB HSCs harvesting, along with the routine methods of their quality control (i.e., HLA typing, testing for infectious pathogens) are listed in brief. Ca. 250,000 CB units are now stored in 35 blood banks in 21 countries worldwide. Some ethical problems with application of CB cells could arise during their long-term storage. The authors point to the controversies associated with the development of private cord blood banks (capacity is estimated at 600,000 CB units), due to indefinite and/or indefensible terms of their storage for eventual transplants. The specific potential of CB HSCs is limited by small sample volume; however relatively low numbers of HSCs with high proliferative activities, along with lower counts of T lymphocytes and their higher immunological tolerance enable HSC transplants at reduced rejection risk and lower GvHD rates.

Clinical experience with CB HSC transplantation is compared for different centers, where the high efficiency of this approach is shown, being, however, associated with longer terms of hematopoietic recovery when compared to bone marrow transplants. A minimal acceptable HSC CB dose is estimated as 1.5-2.5x10⁷ nucleated cells per kg body mass of a patient. The main areas of CB HSC transplantation are described, i.e., related or unrelated transplants, performed in non-cancer and malignant disorders. The authors point to scarce data comparing the efficiency of HSCs derived from cord blood versus bone marrow samples.

Special attention is paid to CB HSC transplantation in non-malignant conditions with bone marrow aplasia associated with unacceptably high non-engraftment risk. Good results of CB HSCT are demonstrated in hemoglobinopathies and mucopolysaccharidoses. When administering CB HSCs to adult patients, non-myeloablative conditioning regimens are proposed, despite the poorly defined efficiency of such an approach. An opportunity for simultaneous transplants of two or more HSC units is considered, including a unit of CB HSCs. An option of intraosseous CB HSC injection is also discussed. In vitro techniques of CB HSC expansion are under development, in spite of scarce data on their proliferative rates and differentiation ability. As an additional stimulus, injection of mesenchymal stem cells together with CB HSCs was recently proposed. In conclusion, the possible usage of normal CB HSCs to correct genetic deficiencies in children is described. CB HSCs' pluripotency may be also applied to the repair of various tissue lesions, e.g., myocardial infarction, or vascular defects.

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¹Pediatric Hemato-Oncology Department, The Edmond and Lily Safra children's Hospital;
²Division of Hematology and Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer and Sackler school of Medicine, Tel Aviv University, Tel Aviv, Israel

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¹Pediatric Hemato-Oncology Department, The Edmond and Lily Safra children's Hospital;
²Division of Hematology and Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer and Sackler school of Medicine, Tel Aviv University, Tel Aviv, Israel

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class="bodytext">Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных. </p> <p class="bodytext">Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга. </p> <p class="bodytext">Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4909) "

Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных.

Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга.

Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).

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Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных.

Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга.

Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).

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Cell therapy in medicine

The idea of utilizing cells for therapeutic purposes is by no means new. The Swiss physician Paul Niehans propagated, as early as 1931, different cell types as tools for rejuvenation and cure against diseases, a therapy he called ‘Zellulartherapie’, which has also been called ‘Frischzelltherapie’ [51]. Niehans treated a patient with tetany with injections of the parathyroid glands of an ox and the patient recovered. He also successfully treated Pope Pious XII. However, the use of animal cells was hampered by considerable side effects and this form of therapy subsequently was banned in Germany [76].

The best-known and most successful example of cell therapy is bone marrow transplantation. Lorenz showed in 1949 that lethally irradiated mice could be rescued by bone marrow cell infusion [43]. A first patient report of intravenous infusion followed by transient engraftment was published in 1957 [68] and in 1968-9 the first matched sibling transplantations were reported [20].  Bone marrow transplantation (BMT) is now established as the first successful cell therapy as a routine procedure for the treatment of formerly incurable leukemias and the pioneer of this therapy, E. Donnall Thomas, received the Nobel Price in Physiology in 1990 [49].

The concept of cell therapy

The initial intention of BMT was to replace the lethally injured and ablated organ with a new one to rescue the patient. However, it was recognized later that the infused bone marrow also has anti-leukemic properties, a phenomenon called graft-versus leukemia effect [32]. This represents a fundamental advantage of cell therapy over pharmaceutical approaches. Furthermore, cells are able to react in vivo depending on the different circumstances under normal and pathophysiological conditions, systemically through secretion of growth factors, cytokines or chemokines as well as through paracrine and local actions at the site of injury. Additionally, cells are able to integrate into tissues, either as differentiated parenchymal cells or as undifferentiated stromal cells, thereby affecting the organ of engraftment in the long run. These versatile properties make the development of cellular therapies promising and attractive.

Multipotent marrow stromal cells (MSCs)

Friedenstein showed that fibroblast like cells could be generated and propagated in vitro from bone marrow and called these cells ‘marrow stromal cells’ [19]. Due to their differentiation into osteocytes, chondrocytes and adipocytes they have also been called ‘mesenchymal stem cells’. These cells support hematopoietic stem cells (HSCs) by growth factor and cytokine secretion and differentiate into bone, cartilage and fat. MSCs have now been recognized as the second stem cell population in the bone marrow, next to HSCs, but can also be generated from almost any organ [10]. They are now defined by plastic adherence, positivity for the surface markers CD73, CD90 and CD105 and absence of CD45, CD34, HLA-DR [15].

Extensive in vitro and in vivo studies have shown that MSCs exhibit a potential to differentiate into various cell types (Graph 1). Lineage analyses of cloned MSCs showed that their natural differentiation pathway (‘default pathway’) is the osteogenic lineage and different clones exhibit different lineage potential in vitro [52]. Differentiation of MSCs into different cell types in vitro can be induced through culture conditions and addition of endogenous substances like steroids, growths factors or PPARs or by demethylation agents like 5-azacytidine [45]. MSCs are not a homogeneous population of cells, in vitro cultures are phenotypically different in size and shape, and can be generated from most organs [79]. MSCs are readily generated from bone marrow aspirations, can be expanded in culture on a large scale without the addition of xenogenic additives like fetal calf serum [37] and are susceptible to transduction with viral vectors which makes them ideal vehicles for cell therapy.

MSCs have been originally derived from the bone marrow by a protocol from Friedenstein, however, with subsequent variation in culture conditions different cell populations with similar but not identical properties like MSCs have been described by various groups. It is currently not entirely clear how these different ‘brands’ of MSCs are related in vivo or if they are derived from a “basic” MSC and how culture conditions, e.g. the addition of growth factors like EGF, a low oxygen environment, low serum conditions and seeding density influence propagation and differentiation potential after several passages in vitro. Verfaillie’s group generated multipotent adult progenitor cells (MAPCs) from the bone marrow under low density and low serum conditions and could show that they have embryonic stem cell like properties when injected into blastocysts [28]. So-called marrow-isolated adult multilineage inducible cells (MIAMI) were generated under low-oxygen tension on fibronectin from bone marrow cells [9]. Lange et al described a population of bone marrow-derived adult stem cells, separated on a Percoll gradient with low density, that showed an extraordinary high proliferative potential and a conserved phenotype characteristic of MSCs [38]. MSCs not only have been derived from bone marrow but from almost any organ [10].

Unrestricted somatic stem cells (USSCs) have been cultured from human cord blood [31]. The authors state that USSCs have a wider differentiation potential and differ in immunophenotype and in their mRNA expression profile. Not all groups have been successful in generating stem cell like cells from cord blood [46]. In contrast to Mareschi, Lee et al. found a mesenchymal stem cell like population derived from cord blood cells with classical characteristics of MSCs as well as differentiation into neuroglial- and hepatocyte-like cells under appropriate induction conditions. Adipose tissue contains MSCs that are easy to obtain from lipoaspirates [81]. Because they are easy to culture and readily available from different sources, MSCs continue to be a popular research subject with steadily increasing numbers of publications and applications.

Mechanisms of action of MSCs used in cell therapy and regenerative medicine

1. Replacement of injured cells by MSCs through differentiation and integration into organ parenchyma

Cellular differentiation is not an irreversible process. Pathologists know the phenomenon of differentiation of one cell type into another due to prolonged exposure to un-physiological stimuli in epithelia, e.g. gastric reflux causes the squamous epithelium of the esophagus to differentiate into gastric mucosa, and have termed it ‘metaplasia’. In the kidney, tubular cells de-differentiate after ischemic injury, re-express embryonic and developmental markers like Pax-2, and start dividing to repopulate the denuded tubular parts, thereby regenerating a sublethally injured tubule [75, 25].

In the late 1990s researchers described so far unknown and unexpected differentiation of HSCs into a number of cell types, e.g. liver and muscle [17, 55]. These results were surprising because a long held dogma stated that adult stem cells are lineage restricted and can only differentiate into tissue from their lineage and that differentiation is terminal [39]. This so called transdifferentiation was immediately recognized as a new and promising way of regeneration of injured tissue and proposed as a mechanism of action for cell therapy. However, initial enthusiasm led researchers to overlook some problems associated with early studies. These studies utilized crude cell preparations, e.g. whole bone marrow, and therefore it was not clear, which cell type was responsible for the observed phenomenon. Furthermore, transdifferentiation was very rare and only some dispersed single cells could be detected after a meticulous search, calling into question the therapeutic value of this approach. Krause et al in a very carefully conducted study showed, that a prospectively isolated HSCs are indeed the cell type responsible for tissue contribution and differentiation into most organ cells, but the contribution was below 0.1% [33].

Some time later two groups described fusion of cells in vitro and it was discussed, that this could be a potential explanation for the phenomena described in the early stem cell studies [67, 78]. Indeed, some groups attributed cell fusion as the main mechanism for organ regeneration in certain disease models [47, 72, 74].

Meticulous studies by Wagers and Balsam showed that transdifferentiation is an extremely rare event under steady state and ischemic conditions and HSCs do not contribute much to tissue turnover [73, 5].

The lessons learned from these studies with HSCs are:

• Transdifferentiation or plasticity is a real phenomenon but exceedingly rare in most disease models.

• Replacement of damaged tissue is therefore not a major mechanism for tissue regeneration.

• Under steady state conditions tissue replacement is rare and in  disease conditions it is dependent on the model and kinetics used to study transdifferentiation.

Based on initial observations with whole bone marrow and the fact that MSCs can be differentiated into a large number of differentiated cells in vitro and in vivo, e.g. neurons [57], cardiomyocytes [45], myocytes [11], endothelial cells [54, 41], pulmonary cells [53] and liver cells [34-36], it was hypothesized that differentiation of MSCs into organ parenchymal cells is a major mechanism of tissue protection and regeneration after injury. However, MCSs exhibited tissue repair capacity despite low or transient engraftment in vivo, e.g. in the treatment of osteogenesis imperfecta it was less than 1% [22], and therefore differentiation into target tissues is most likely only a minor mechanisms of tissue protection and regeneration. The fact that tissue protection is observed without evidence of long-term engraftment also argues against differentiation as a main mechanism of action [27].

2. Paracrine mechanisms

MSCs produce a number of cytokines, growth factors and adhesion molecules that have been shown to be involved in tissue homeostasis and regeneration [13]. Furthermore, transcriptome analysis by serial analysis of gene expression (SAGE) revealed a large number of transcripts for proteins involved in wound repair, immunological regulation, neural factors as well as angiogenesis [70, 56] implying a role for these factors in MSC mediated tissue regeneration. These factors stimulate cell proliferation (growth factors like IGF [24]) and are anti-apoptotic [7]. The advantage of administering MSCs rather than growth factors directly lies in the fact that MSCs act on a local level and are able to interact with damaged tissue, which means they probably respond to cytokines like TNF-a secreted by damaged tissue with more or less secretion of a number of growth factors or modulatory cytokines and thereby influence the local environment directly and better than any systemically administered growth factors [41, 62]. In the kidney, MSCs regenerate renal function after acute kidney injury mainly by secreting epidermal growth factor (EGF), insulin-like growth factor (IGF-1), VEGF and by changing the cytokine expression profile of the injured kidney towards a more favorable anti-inflammatory state with higher IL-10 levels [60, 69]. In the heart, MSCs stimulate angiogenesis by secretion of VEGF [1, 29]. Endogenous cell proliferation in the brain is stimulated by MSCs through paracrine mechanisms after injury mediated by different factors [44, 8].

3. Vasculo- and angiogenesis

Blood supply is the most critical factor for tissue survival and most injury mechanisms involve the vasculature in one way or another. Ischemic injury is the most common mechanism of tissue damage for every organ system and fast restoration of regular blood supply is critical for tissue survival. The microvascular bed can be damaged in many ways, but endothelial dysfunction or apoptosis are major factors. MSCs express a number of angiogenic and vasculogenic factors and proteins that have been shown to increase endothelial cell survival and proliferation [2, 23]. In vivo studies have shown that vasculo- and angiogenesis by MSCs is either mediated directly by integration into vascular structures or through paracrine mechanisms stimulating angiogenesis, e.g. secretion of VEGF, angiopoietin or other growth factors [2, 3, 65, 64, 77]. MSCs can be genetically engineered, using different strategies like bcl-2, Akt or erythropoietin expression, to enhance endogenous angiogenic activity [16, 21].

4. Immunomodulation

MSCs exhibit low immunogenity due to low or absent MHC-II expression, low MHC-I expression and negativity for costimulatory molecules CD80, CD86 and CD40. Therefore infusion of MSCs do not trigger a direct rejection reaction, although several groups have shown that MSCs are not neutral towards the immune system and antibodies can be measured as well as T cell activation but not proliferation [30, 58]. A large body of data shows immunomodulatory properties of MSCs in vitro on different cell types such as T-cells, B-cells and NK cells [18]. MSCs suppress T-cell proliferation in vitro, interfere with dendritic cell differentiation, inhibit B-cell proliferation and suppress the proliferation and cytokine production of natural killer cells [50]. The in vivo relevance of these in vitro finding has been demonstrated in humans with acute graft versus host (GvHD) and Crohn’s disease [61, 66]. In animal models MSCs have been shown to modify experimental autoimmune encephalitis, a model of multiple sclerosis, and prolonged skin graft survival in baboons [6, 71]. There are conflicting data about effects of MSCs in organ transplantation models. Inoue reported that MSCs were ineffective at prolonging allograft survival and tended to promote rejection [26]. In a different model cardiac allograft survival was prolonged [80]. MSCs also favored tumour survival in animal models [14].

While the currently known immunomodulatory effects of MSCs show promise for the treatment of a number of diseases, data have to be interpreted carefully dependent on the animal model or in vitro strategy. Culture conditions and numerous other factors not least the model that is studied play important roles and have to be considered carefully to avoid preliminary conclusions.

5. Other applications for MSCs

MSCs are ideally suited as cellular delivery systems in tumor treatment. They can be engineered to express the interferon-beta (IFN-beta) gene and deliver therapeutic doses of IFN-beta directly into the tumor through infiltration thereby suppressing tumor growth and metastasis [63]. In metabolic diseases and enzyme defects, either allogeneic or genetically engineered MSCs are able to function as enzyme replacement therapy [48] by providing necessary concentrations of an enzyme that is lacking due to a genetic defect. MSCs are rapidly transducable with different viral vectors and are thereby ideal vehicles for therapeutic genes [59]. Other important applications include adjunct infusion to enhance hematopoietic engraftment [4] and as a source for engineered tissue such as cartilage and bone in tissue engineering [12].

Conclusions

In the ongoing story of stem cell treatment for patients MSCs have been so far the most promising development and have rapidly advanced from bench to bedside with several products already in late stage trials. Although little is known about MSCs in vivo, they have been characterized extensively in vitro and clinical studies have been finished and new ones are on their way. The mechanisms of action of MSCs are currently investigated in detail and there is still a large number of questions to be addressed until the full therapeutic benefit of these cells can be utilized but the field is rapidly advancing and is giving a shining example for the whole stem cell community. 

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Cell therapy in medicine

The idea of utilizing cells for therapeutic purposes is by no means new. The Swiss physician Paul Niehans propagated, as early as 1931, different cell types as tools for rejuvenation and cure against diseases, a therapy he called ‘Zellulartherapie’, which has also been called ‘Frischzelltherapie’ [51]. Niehans treated a patient with tetany with injections of the parathyroid glands of an ox and the patient recovered. He also successfully treated Pope Pious XII. However, the use of animal cells was hampered by considerable side effects and this form of therapy subsequently was banned in Germany [76].

The best-known and most successful example of cell therapy is bone marrow transplantation. Lorenz showed in 1949 that lethally irradiated mice could be rescued by bone marrow cell infusion [43]. A first patient report of intravenous infusion followed by transient engraftment was published in 1957 [68] and in 1968-9 the first matched sibling transplantations were reported [20].  Bone marrow transplantation (BMT) is now established as the first successful cell therapy as a routine procedure for the treatment of formerly incurable leukemias and the pioneer of this therapy, E. Donnall Thomas, received the Nobel Price in Physiology in 1990 [49].

The concept of cell therapy

The initial intention of BMT was to replace the lethally injured and ablated organ with a new one to rescue the patient. However, it was recognized later that the infused bone marrow also has anti-leukemic properties, a phenomenon called graft-versus leukemia effect [32]. This represents a fundamental advantage of cell therapy over pharmaceutical approaches. Furthermore, cells are able to react in vivo depending on the different circumstances under normal and pathophysiological conditions, systemically through secretion of growth factors, cytokines or chemokines as well as through paracrine and local actions at the site of injury. Additionally, cells are able to integrate into tissues, either as differentiated parenchymal cells or as undifferentiated stromal cells, thereby affecting the organ of engraftment in the long run. These versatile properties make the development of cellular therapies promising and attractive.

Multipotent marrow stromal cells (MSCs)

Friedenstein showed that fibroblast like cells could be generated and propagated in vitro from bone marrow and called these cells ‘marrow stromal cells’ [19]. Due to their differentiation into osteocytes, chondrocytes and adipocytes they have also been called ‘mesenchymal stem cells’. These cells support hematopoietic stem cells (HSCs) by growth factor and cytokine secretion and differentiate into bone, cartilage and fat. MSCs have now been recognized as the second stem cell population in the bone marrow, next to HSCs, but can also be generated from almost any organ [10]. They are now defined by plastic adherence, positivity for the surface markers CD73, CD90 and CD105 and absence of CD45, CD34, HLA-DR [15].

Extensive in vitro and in vivo studies have shown that MSCs exhibit a potential to differentiate into various cell types (Graph 1). Lineage analyses of cloned MSCs showed that their natural differentiation pathway (‘default pathway’) is the osteogenic lineage and different clones exhibit different lineage potential in vitro [52]. Differentiation of MSCs into different cell types in vitro can be induced through culture conditions and addition of endogenous substances like steroids, growths factors or PPARs or by demethylation agents like 5-azacytidine [45]. MSCs are not a homogeneous population of cells, in vitro cultures are phenotypically different in size and shape, and can be generated from most organs [79]. MSCs are readily generated from bone marrow aspirations, can be expanded in culture on a large scale without the addition of xenogenic additives like fetal calf serum [37] and are susceptible to transduction with viral vectors which makes them ideal vehicles for cell therapy.

MSCs have been originally derived from the bone marrow by a protocol from Friedenstein, however, with subsequent variation in culture conditions different cell populations with similar but not identical properties like MSCs have been described by various groups. It is currently not entirely clear how these different ‘brands’ of MSCs are related in vivo or if they are derived from a “basic” MSC and how culture conditions, e.g. the addition of growth factors like EGF, a low oxygen environment, low serum conditions and seeding density influence propagation and differentiation potential after several passages in vitro. Verfaillie’s group generated multipotent adult progenitor cells (MAPCs) from the bone marrow under low density and low serum conditions and could show that they have embryonic stem cell like properties when injected into blastocysts [28]. So-called marrow-isolated adult multilineage inducible cells (MIAMI) were generated under low-oxygen tension on fibronectin from bone marrow cells [9]. Lange et al described a population of bone marrow-derived adult stem cells, separated on a Percoll gradient with low density, that showed an extraordinary high proliferative potential and a conserved phenotype characteristic of MSCs [38]. MSCs not only have been derived from bone marrow but from almost any organ [10].

Unrestricted somatic stem cells (USSCs) have been cultured from human cord blood [31]. The authors state that USSCs have a wider differentiation potential and differ in immunophenotype and in their mRNA expression profile. Not all groups have been successful in generating stem cell like cells from cord blood [46]. In contrast to Mareschi, Lee et al. found a mesenchymal stem cell like population derived from cord blood cells with classical characteristics of MSCs as well as differentiation into neuroglial- and hepatocyte-like cells under appropriate induction conditions. Adipose tissue contains MSCs that are easy to obtain from lipoaspirates [81]. Because they are easy to culture and readily available from different sources, MSCs continue to be a popular research subject with steadily increasing numbers of publications and applications.

Mechanisms of action of MSCs used in cell therapy and regenerative medicine

1. Replacement of injured cells by MSCs through differentiation and integration into organ parenchyma

Cellular differentiation is not an irreversible process. Pathologists know the phenomenon of differentiation of one cell type into another due to prolonged exposure to un-physiological stimuli in epithelia, e.g. gastric reflux causes the squamous epithelium of the esophagus to differentiate into gastric mucosa, and have termed it ‘metaplasia’. In the kidney, tubular cells de-differentiate after ischemic injury, re-express embryonic and developmental markers like Pax-2, and start dividing to repopulate the denuded tubular parts, thereby regenerating a sublethally injured tubule [75, 25].

In the late 1990s researchers described so far unknown and unexpected differentiation of HSCs into a number of cell types, e.g. liver and muscle [17, 55]. These results were surprising because a long held dogma stated that adult stem cells are lineage restricted and can only differentiate into tissue from their lineage and that differentiation is terminal [39]. This so called transdifferentiation was immediately recognized as a new and promising way of regeneration of injured tissue and proposed as a mechanism of action for cell therapy. However, initial enthusiasm led researchers to overlook some problems associated with early studies. These studies utilized crude cell preparations, e.g. whole bone marrow, and therefore it was not clear, which cell type was responsible for the observed phenomenon. Furthermore, transdifferentiation was very rare and only some dispersed single cells could be detected after a meticulous search, calling into question the therapeutic value of this approach. Krause et al in a very carefully conducted study showed, that a prospectively isolated HSCs are indeed the cell type responsible for tissue contribution and differentiation into most organ cells, but the contribution was below 0.1% [33].

Some time later two groups described fusion of cells in vitro and it was discussed, that this could be a potential explanation for the phenomena described in the early stem cell studies [67, 78]. Indeed, some groups attributed cell fusion as the main mechanism for organ regeneration in certain disease models [47, 72, 74].

Meticulous studies by Wagers and Balsam showed that transdifferentiation is an extremely rare event under steady state and ischemic conditions and HSCs do not contribute much to tissue turnover [73, 5].

The lessons learned from these studies with HSCs are:

• Transdifferentiation or plasticity is a real phenomenon but exceedingly rare in most disease models.

• Replacement of damaged tissue is therefore not a major mechanism for tissue regeneration.

• Under steady state conditions tissue replacement is rare and in  disease conditions it is dependent on the model and kinetics used to study transdifferentiation.

Based on initial observations with whole bone marrow and the fact that MSCs can be differentiated into a large number of differentiated cells in vitro and in vivo, e.g. neurons [57], cardiomyocytes [45], myocytes [11], endothelial cells [54, 41], pulmonary cells [53] and liver cells [34-36], it was hypothesized that differentiation of MSCs into organ parenchymal cells is a major mechanism of tissue protection and regeneration after injury. However, MCSs exhibited tissue repair capacity despite low or transient engraftment in vivo, e.g. in the treatment of osteogenesis imperfecta it was less than 1% [22], and therefore differentiation into target tissues is most likely only a minor mechanisms of tissue protection and regeneration. The fact that tissue protection is observed without evidence of long-term engraftment also argues against differentiation as a main mechanism of action [27].

2. Paracrine mechanisms

MSCs produce a number of cytokines, growth factors and adhesion molecules that have been shown to be involved in tissue homeostasis and regeneration [13]. Furthermore, transcriptome analysis by serial analysis of gene expression (SAGE) revealed a large number of transcripts for proteins involved in wound repair, immunological regulation, neural factors as well as angiogenesis [70, 56] implying a role for these factors in MSC mediated tissue regeneration. These factors stimulate cell proliferation (growth factors like IGF [24]) and are anti-apoptotic [7]. The advantage of administering MSCs rather than growth factors directly lies in the fact that MSCs act on a local level and are able to interact with damaged tissue, which means they probably respond to cytokines like TNF-a secreted by damaged tissue with more or less secretion of a number of growth factors or modulatory cytokines and thereby influence the local environment directly and better than any systemically administered growth factors [41, 62]. In the kidney, MSCs regenerate renal function after acute kidney injury mainly by secreting epidermal growth factor (EGF), insulin-like growth factor (IGF-1), VEGF and by changing the cytokine expression profile of the injured kidney towards a more favorable anti-inflammatory state with higher IL-10 levels [60, 69]. In the heart, MSCs stimulate angiogenesis by secretion of VEGF [1, 29]. Endogenous cell proliferation in the brain is stimulated by MSCs through paracrine mechanisms after injury mediated by different factors [44, 8].

3. Vasculo- and angiogenesis

Blood supply is the most critical factor for tissue survival and most injury mechanisms involve the vasculature in one way or another. Ischemic injury is the most common mechanism of tissue damage for every organ system and fast restoration of regular blood supply is critical for tissue survival. The microvascular bed can be damaged in many ways, but endothelial dysfunction or apoptosis are major factors. MSCs express a number of angiogenic and vasculogenic factors and proteins that have been shown to increase endothelial cell survival and proliferation [2, 23]. In vivo studies have shown that vasculo- and angiogenesis by MSCs is either mediated directly by integration into vascular structures or through paracrine mechanisms stimulating angiogenesis, e.g. secretion of VEGF, angiopoietin or other growth factors [2, 3, 65, 64, 77]. MSCs can be genetically engineered, using different strategies like bcl-2, Akt or erythropoietin expression, to enhance endogenous angiogenic activity [16, 21].

4. Immunomodulation

MSCs exhibit low immunogenity due to low or absent MHC-II expression, low MHC-I expression and negativity for costimulatory molecules CD80, CD86 and CD40. Therefore infusion of MSCs do not trigger a direct rejection reaction, although several groups have shown that MSCs are not neutral towards the immune system and antibodies can be measured as well as T cell activation but not proliferation [30, 58]. A large body of data shows immunomodulatory properties of MSCs in vitro on different cell types such as T-cells, B-cells and NK cells [18]. MSCs suppress T-cell proliferation in vitro, interfere with dendritic cell differentiation, inhibit B-cell proliferation and suppress the proliferation and cytokine production of natural killer cells [50]. The in vivo relevance of these in vitro finding has been demonstrated in humans with acute graft versus host (GvHD) and Crohn’s disease [61, 66]. In animal models MSCs have been shown to modify experimental autoimmune encephalitis, a model of multiple sclerosis, and prolonged skin graft survival in baboons [6, 71]. There are conflicting data about effects of MSCs in organ transplantation models. Inoue reported that MSCs were ineffective at prolonging allograft survival and tended to promote rejection [26]. In a different model cardiac allograft survival was prolonged [80]. MSCs also favored tumour survival in animal models [14].

While the currently known immunomodulatory effects of MSCs show promise for the treatment of a number of diseases, data have to be interpreted carefully dependent on the animal model or in vitro strategy. Culture conditions and numerous other factors not least the model that is studied play important roles and have to be considered carefully to avoid preliminary conclusions.

5. Other applications for MSCs

MSCs are ideally suited as cellular delivery systems in tumor treatment. They can be engineered to express the interferon-beta (IFN-beta) gene and deliver therapeutic doses of IFN-beta directly into the tumor through infiltration thereby suppressing tumor growth and metastasis [63]. In metabolic diseases and enzyme defects, either allogeneic or genetically engineered MSCs are able to function as enzyme replacement therapy [48] by providing necessary concentrations of an enzyme that is lacking due to a genetic defect. MSCs are rapidly transducable with different viral vectors and are thereby ideal vehicles for therapeutic genes [59]. Other important applications include adjunct infusion to enhance hematopoietic engraftment [4] and as a source for engineered tissue such as cartilage and bone in tissue engineering [12].

Conclusions

In the ongoing story of stem cell treatment for patients MSCs have been so far the most promising development and have rapidly advanced from bench to bedside with several products already in late stage trials. Although little is known about MSCs in vivo, they have been characterized extensively in vitro and clinical studies have been finished and new ones are on their way. The mechanisms of action of MSCs are currently investigated in detail and there is still a large number of questions to be addressed until the full therapeutic benefit of these cells can be utilized but the field is rapidly advancing and is giving a shining example for the whole stem cell community. 

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Тегель Ф., Вестенфельдер Кр.

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Обзорная статья  содержит сведения об историческом развити и общей концепции клеточной терапии в медицине. Помимо заместительной функции трансплантата при трансплантации костного мозга (ТКМ), рассматриваются другие лечебные эффекты трансплантата (противоопухолевое действие, стимуляция иммунного ответа и др.). Основной материал работы касается мультипотентных стромальных клеток костного мозга (МСК), описаны их фенотипические признаки (CD73+, CD90+, CD105+, CD45-, CD34-, HLA-DR-). Обсуждаются возможности МСК к дифференцировке in vitro и роль различных условий культивирования на их мультипотентность и направленность дифференцировки.  Пластичность МСК взрослого организма в плане трансдифференцировки (например, в ткани мышц или печени) может быть в редких случаях одним из источников регенерации. Более вероятны паракринные механизмы действия МСК, а именно выработка ими множества цитокинов, факторов роста и адгезии, что иллюстрируется экспериментальными данными о регенерации почек, сердца и головного мозга. В качестве отдельных механизмов рассматривается инлукция ангиогенеза и модуляция Т- и В-лимфоцитов под влиянием МСК. Делается заключение о необходимости дальнейших исследований клинически актуальных эффектов МСК.

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Florian Tögel, Christof Westenfelder

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Department of Medicine/Nephrology and VA Medical Center, University of Utah, USA

Correspondence:
University of Utah, Department of Medicine/Nephrology and VA Medical Center, Nephrology Research Laboratory (151M), 500 Foothill Blvd, Salt Lake City, UT 84148, USA

E-mail: Florian.Toegel@hsc.utah.edu or Christof.Westenfelder@hsc.utah.edu

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Cell therapy has become a promising new treatment approach for a large number of different diseases, and applications are continually being developed. Bone marrow derived stem cells are currently being tested in clinical trials and have been shown to be promising new therapeutic vehicles. Multipotent marrow stromal cells (MSCs) are a bone marrow derived cell type that can be easily cultured and expanded in vitro and have a broad range of potential and actual therapeutic applications. The mechanism of action of MSCs in the therapeutic situation depends on the disease, and involves differentiation, immunomodulation, paracrine, and anti-apoptotic mechanisms. These mechanisms are discussed in detail in this manuscript.

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Florian Tögel, Christof Westenfelder

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Florian Tögel, Christof Westenfelder

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Cell therapy has become a promising new treatment approach for a large number of different diseases, and applications are continually being developed. Bone marrow derived stem cells are currently being tested in clinical trials and have been shown to be promising new therapeutic vehicles. Multipotent marrow stromal cells (MSCs) are a bone marrow derived cell type that can be easily cultured and expanded in vitro and have a broad range of potential and actual therapeutic applications. The mechanism of action of MSCs in the therapeutic situation depends on the disease, and involves differentiation, immunomodulation, paracrine, and anti-apoptotic mechanisms. These mechanisms are discussed in detail in this manuscript.

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Cell therapy has become a promising new treatment approach for a large number of different diseases, and applications are continually being developed. Bone marrow derived stem cells are currently being tested in clinical trials and have been shown to be promising new therapeutic vehicles. Multipotent marrow stromal cells (MSCs) are a bone marrow derived cell type that can be easily cultured and expanded in vitro and have a broad range of potential and actual therapeutic applications. The mechanism of action of MSCs in the therapeutic situation depends on the disease, and involves differentiation, immunomodulation, paracrine, and anti-apoptotic mechanisms. These mechanisms are discussed in detail in this manuscript.

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Department of Medicine/Nephrology and VA Medical Center, University of Utah, USA

Correspondence:
University of Utah, Department of Medicine/Nephrology and VA Medical Center, Nephrology Research Laboratory (151M), 500 Foothill Blvd, Salt Lake City, UT 84148, USA

E-mail: Florian.Toegel@hsc.utah.edu or Christof.Westenfelder@hsc.utah.edu

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Department of Medicine/Nephrology and VA Medical Center, University of Utah, USA

Correspondence:
University of Utah, Department of Medicine/Nephrology and VA Medical Center, Nephrology Research Laboratory (151M), 500 Foothill Blvd, Salt Lake City, UT 84148, USA

E-mail: Florian.Toegel@hsc.utah.edu or Christof.Westenfelder@hsc.utah.edu

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Тегель Ф., Вестенфельдер Кр.

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Тегель Ф., Вестенфельдер Кр.

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string(2292) "<p class="bodytext">Обзорная статья  содержит сведения об историческом развити и общей концепции клеточной терапии в медицине. Помимо заместительной функции трансплантата при трансплантации костного мозга (ТКМ), рассматриваются другие лечебные эффекты трансплантата (противоопухолевое действие, стимуляция иммунного ответа и др.). Основной материал работы касается мультипотентных стромальных клеток костного мозга (МСК), описаны их фенотипические признаки (CD73+, CD90+, CD105+, CD45-, CD34-, HLA-DR-). Обсуждаются возможности МСК к дифференцировке in vitro и роль различных условий культивирования на их мультипотентность и направленность дифференцировки.  Пластичность МСК взрослого организма в плане трансдифференцировки (например, в ткани мышц или печени) может быть в редких случаях одним из источников регенерации. Более вероятны паракринные механизмы действия МСК, а именно выработка ими множества цитокинов, факторов роста и адгезии, что иллюстрируется экспериментальными данными о регенерации почек, сердца и головного мозга. В качестве отдельных механизмов рассматривается инлукция ангиогенеза и модуляция Т- и В-лимфоцитов под влиянием МСК. Делается заключение о необходимости дальнейших исследований клинически актуальных эффектов МСК. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2270) "

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Обзорная статья  содержит сведения об историческом развити и общей концепции клеточной терапии в медицине. Помимо заместительной функции трансплантата при трансплантации костного мозга (ТКМ), рассматриваются другие лечебные эффекты трансплантата (противоопухолевое действие, стимуляция иммунного ответа и др.). Основной материал работы касается мультипотентных стромальных клеток костного мозга (МСК), описаны их фенотипические признаки (CD73+, CD90+, CD105+, CD45-, CD34-, HLA-DR-). Обсуждаются возможности МСК к дифференцировке in vitro и роль различных условий культивирования на их мультипотентность и направленность дифференцировки.  Пластичность МСК взрослого организма в плане трансдифференцировки (например, в ткани мышц или печени) может быть в редких случаях одним из источников регенерации. Более вероятны паракринные механизмы действия МСК, а именно выработка ими множества цитокинов, факторов роста и адгезии, что иллюстрируется экспериментальными данными о регенерации почек, сердца и головного мозга. В качестве отдельных механизмов рассматривается инлукция ангиогенеза и модуляция Т- и В-лимфоцитов под влиянием МСК. Делается заключение о необходимости дальнейших исследований клинически актуальных эффектов МСК.

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                    [TEXT] => <p class="bodytext">Множественная миелома (<strong>ММ</strong>)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (<strong>МК</strong>), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов. 
</p>
<p class="bodytext"><strong>HGF является фактором аутокринной стимуляции МК.</strong>  <strong>Экспрессия </strong><strong>HGF характерна для МК и отличает ММ от родственных опухолей. </strong>МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген <em>HGF</em> является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена <em>HGF</em> была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген <em>HGF</em> включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.<br /><br /><strong>Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. </strong>Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.<br /><br />До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (<em>RANKL, </em><em>RANK, </em><em>OPG, </em><em>MIP1</em><em><img v:shapes="_x0000_i1025" src="file:///C:%5CDOKUME~1%5COksana%5CLOKALE~1%5CTemp%5Cmsohtml1%5C01%5Cclip_image002.gif" width="8" height="6" alt="" />, </em><em>PTHrP,</em> и <em>IL1)</em>, а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.<br /><br /><strong>HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (</strong><strong>BMP). </strong>HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ. 
</p>
<p class="bodytext"><strong>HGF и </strong><strong>c-</strong><strong>Met как потенциальные мишени терапии. </strong>Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес.
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Множественная миелома (ММ)  - это плазмоклеточная злокачественная опухоль с поражением костного мозга,  которая сопровождается продукцией моноклонального иммуноглобулина, анемией и деструкцией кости. Неизлечима. Генетическая основа ММ гетерогенна: в приблизительно половине наблюдений ММ  имеются транслокации с участием, с одной стороны,  хромосомы 14 (ген IgH), и с другой – ряда хромосом с точкой разрыва вблизи локализации различных онкогенов.  Эти мутации относятся к раннему онкогенезу.  В остальных случаях наблюдается гипердиплоидия с трисомиями нечетных хромосом. Вне зависимости от характера генетического дефекта в опухолевых клетках обнаруживается гиперэкспрессия циклинов D. Миеломные клетки (МК), как правило, не растут в искусственных средах; это позволяет считать, что они критически зависимы от ряда еще не известных факторов, которые содержатся в костном мозге. МК стимулируют рост сосудов и функцию остеокластов. 

HGF является фактором аутокринной стимуляции МК.  Экспрессия HGF характерна для МК и отличает ММ от родственных опухолей. МК часто коэкспрессируют HGF и его рецептор c-Met и могут секретировать вещества, переводящие HGF в активную форму,  в т.ч. активатор плазминогена. Маркер плазматических клеток CD138 (синдекан-1) является корецептором HGF. HGF стимулирует миграцию и адгезию МК и таким образом может иметь значение в удержании МК в костном мозге. Кроме того, HGF, по видимому, стимулирует ангиогенез. Ген HGF является единственным из 70 генов факторов роста, и единственным из генов, кодирующих проангиогенные белки,  гиперэкспрессированным в МК, по сравнению с нормальными плазматическими клетками. Гиперэкспрессия гена HGF была обнаружена и у части больных с MGUS (моноклональная гаммапатия неясного значения), указывая на вероятную роль HGF на ранних этапах опухолевого роста. Показано, что ген HGF включен в состав короткого фрагмента из 4 генов, который амплифицирован у значительной части больных ММ. При этом гиперэкспрессия HGF не обнаруживается у больных хроническим лимфолейкозом (ХЛЛ) и макроглобулинемией Вальденстрема. Высокие уровни HGF в сыворотке больных ММ ассоциированы с неблагоприятным прогнозом.

Нарушения регуляции гомеостаза кости у больных ММ.  Подавление остеогенеза не менее важно, чем стимуляция резорбции. Деструкция кости -  одно из важнейших проявлений ММ. Гомеостаз кости во многом определяется балансом двух белковых продуктов остеобластов – RANKL (необходим для созревания остеокластов) и остеопротегерина (растворимый рецептор-ловушка для RANKL). При ММ концентрация растворимого OPG в костном мозге ниже, а концентрация RANKL – выше, чем у здоровых. МК способны связывать OPG, по видимому, с помощью синдекана-1, с последующей интернализацией и деградацией.

До настоящего времени не обнаружено связи между  степенью выраженности костного синдрома и активацией генов важнейших факторов, стимулирующих остеокласты (RANKL, RANK, OPG, MIP1, PTHrP, и IL1), а также различий экспрессии этих генов при ММ,  ХЛЛ и макроглобулинемии Вальденстрема. В то же время показано, что экспрессия DKK-1 (ингибитор Wnt-зависимого сигналинга, ингибирует дифференцировку предшественников остеобластов) при ММ пропорциональна тяжести костной патологии.

HGF ингибирует дифференцировку мезенхимальных стволовых клеток в остеобласты, индуцированную морфогенетическими протеинами кости (BMP). HGF стимулирует резорбцию кости остеокластами, но только в присутствии остеобластов. Частично этот эффект может объясняться продукцией IL-11 остеобластами под действием HGF. Основным индуктором остеобластической дифференцировки мезенхимальных стволовых клеток являются морфогенетические белки кости (BMP). HGF стимулирует пролиферацию и тормозит дифференцировку мезенхимальных стволовых клеток, несмотря на присутствие BMP.   В результате недостаточно дифференцированные остеобласты еще не способны к синтезу кости, но уже  экспрессируют на своей поверхности RANKL – белок, стимулирующий остеокласты. В пользу существования такого механизма говорит и сильная отрицательная связь между концентрацией HGF и остеоспецифической щелочной фосфатазы (маркер активности остеобластов) в сыворотке крови больных ММ. 

HGF и c-Met как потенциальные мишени терапии. Учитывая многогранность эффектов HGF в отношении миеломных клеток и их микроокружения, рассматривается возможность использования антагонистов HGF/c-Met в качестве лекарственных средств.   Ингибиторы HGF/c-Met включают низкомолекулярные ингибиторы, антитела и естественные сплайс-варианты HGF с полным или частичным антагонизмом. К последним относится NK4,  представляющий собой часть молекулы  HGF. NK4 блокирует рост миеломных клеточных линий в мышиной модели, вероятно, путем прямого торможения пролиферации МК и опосредованного торможения роста сосудов. К группе низкомолекулярных ингибиторов c-Met относится PHA-665752 (Pfizer). В наших экспериментах PHA-665752 подавлял стимуляцию c-Met и ее последствия как в клеточных линиях, так и в клетках пациентов с ММ.  Результаты возможного клинического применения ингибиторов HGF/c-Met представляют несомненный интерес.

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<b>Corresponding author: </b><br>
Magne Børset, Norwegian University of Science and Technology, Faculty of Medicine, Department of Cancer Research and Molecular Medicine, Medical Technical Research Center, N-7489 Trondheim, Norway<br>
 <p>Telephone: + 47 72573038, <br>
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1Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; 2Department of Immunology and Transfusion medicine, St. Olavs University Hospital, Trondheim, Norway; 3 Department of Hematology, St. Olavs University Hospital, Trondheim, Norway.


Corresponding author: 

Magne Børset, Norwegian University of Science and Technology, Faculty of Medicine, Department of Cancer Research and Molecular Medicine, Medical Technical Research Center, N-7489 Trondheim, Norway

 
Telephone: + 47 72573038, 

Fax: + 47 73598801, 
E-mail: magne.borset@ntnu.no

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	 HGF is emerging as a cytokine with an important role in the pathophysiology of multiple myeloma. Originally identified and described as a growth factor for hepatocytes, HGF was later found to have mitogenic, motogenic, or morphogenic effects on several cell types through its interaction with the tyrosine kinase receptor c-Met. This cytokine–receptor pair is implicated in the development and promotion of several types of cancer. The expression of both HGF and c-Met by myeloma cells is one of the traits distinguishing these cells from healthy plasma cells, and seems to be an early step in tumor development. HGF and c-Met have an effect on proliferation, migration, and adhesion of myeloma cells; and research suggests that myeloma cell-produced HGF is an important factor in angiogenesis and bone destruction seen in the majority of patients with multiple myeloma.
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                    [TEXT] => <p class="bodytext">Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных. 
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<p class="bodytext">Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга. 
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<p class="bodytext">Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).</p>
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Обзор посвящен вопросам трансплантации гемопоэтических стволовых клеток из пуповинной крови (ГСК ПК), который ранее применялся в детской практике. Кратко перечислены процедуры сбора ГСК ПК во время родов, а также рутинные тесты оценки их качества (HLA-типирование, проверка инфекционных агентов). Сейчас в мире около 250000 доз ГСК ПК хранятся в 35 банках 21 страны. Этические проблемы с применением  клеток ПК могут возникать при их длительном хранении. Указывается на противоречия, связанные с развитием частных банков пуповинной крови (по оценкам, в них хранятся ок.600000 доз ПК), ввиду неопределенности сроков гарантированного хранения стволовых клеток для возможной трансплантации. Свойства ПК как источника ГСК ограничены небольшим объемом образца и малым числом ГСК, обладающих высокой пролиферативной активностью, при меньшем содержании Т-клеток и их большей иммунологической толерантностью. Это дает возможность проводить пересадки, с меньшими ограничениями по HLA-совместимости, при меньшем риске отторжения и более низкой частоте РТПХ у больных. 

Авторы обобщают клинический опыт ТГСК ПК в различных центрах, где показана высокая эффективность этого метода при более длительных сроках восстановления гемопоэза, чем трансплантации костного мозга. Минимально допустимой дозой ГСК ПК считается 1,5-2,5X107 миелокариоцитов на 1 кг массы тела больного. Описываются основные области применения ГСК ПК (родственная или неродственная трансплантация у детей при неопухолевых и злокачественных и заболеваниях). Подчеркивается нехватка сравнительных данных об эффективности ГСК из пуповинной крови и костного мозга. 

Особое внимание уделяется ТГСК ПК при неопухолевых заболеваниях с аплазией костного мозга, где риск неприживления оказался недопустимо высоким. Описаны хорошие результаты ТГСК ПК при гемоглобинопатиях, мукополисахаридозах. При лечении взрослых больных посредством ТГСК ПК предлагаются немиелоаблативные режимы кондиционирования, хотя эффективность такого подхода пока неясна. Обсуждается возможность одновременной трансплантации двух и более доз ГСК от разных доноров, включая дозу ПК. Дискутируется вопрос о внутрикостном введении ГСК ПК, разрабатываются методы культивирования ГСК ПК в культуре, хотя темпы их размножения этих клеток пока недостаточны, а их способность к дифференцировке мало изучена. В качестве добавочного стимула предложено введение мезенхимных стволовых клеток совместно с ГСК ПК.  В заключение описывается использование нормальных ГСК ПК для коррекции генетических дефектов у детей, а также их плюрипотентность для репарации дефектов других тканей (например, миокарда или сосудов).
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Gal Goldstein1, Amos Toren1, Arnon Nagler2
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1Pediatric Hemato-Oncology Department, The Edmond and Lily Safra children's Hospital;
 2Division of Hematology and Cord Blood Bank, Chaim Sheba Medical Center, Tel Hashomer and Sackler school of Medicine, Tel Aviv University, Tel Aviv, Israel

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                    [TEXT] => <p class="bodytext">The review article concerns the transplantation of hematopoietic stem cells (HSCs) derived from cord blood (CB). This approach was previously used in pediatric settings. In partu procedures of CB HSCs harvesting, along with the routine methods of their quality control (i.e., HLA typing, testing for infectious pathogens) are listed in brief. Ca. 250,000 CB units are now stored in 35 blood banks in 21 countries worldwide. Some ethical problems with application of CB cells could arise during their long-term storage. The authors point to the controversies associated with the development of private cord blood banks (capacity is estimated at 600,000 CB units), due to indefinite and/or indefensible terms of their storage for eventual transplants. The specific potential of CB HSCs is limited by small sample volume; however relatively low numbers of HSCs with high proliferative activities, along with lower counts of T lymphocytes and their higher immunological tolerance enable HSC transplants at reduced rejection risk and lower GvHD rates.
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The review article concerns the transplantation of hematopoietic stem cells (HSCs) derived from cord blood (CB). This approach was previously used in pediatric settings. In partu procedures of CB HSCs harvesting, along with the routine methods of their quality control (i.e., HLA typing, testing for infectious pathogens) are listed in brief. Ca. 250,000 CB units are now stored in 35 blood banks in 21 countries worldwide. Some ethical problems with application of CB cells could arise during their long-term storage. The authors point to the controversies associated with the development of private cord blood banks (capacity is estimated at 600,000 CB units), due to indefinite and/or indefensible terms of their storage for eventual transplants. The specific potential of CB HSCs is limited by small sample volume; however relatively low numbers of HSCs with high proliferative activities, along with lower counts of T lymphocytes and their higher immunological tolerance enable HSC transplants at reduced rejection risk and lower GvHD rates.

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                    [TEXT] => <p>Department of Medicine/Nephrology and VA Medical Center, University of Utah, USA</p><br>

<p><b>Correspondence:</b><br>
 University of Utah, Department of Medicine/Nephrology and VA Medical Center, Nephrology Research Laboratory (151M), 500 Foothill Blvd, Salt Lake City, UT 84148, USA </p><br>
<p>E-mail: Florian.Toegel@hsc.utah.edu or Christof.Westenfelder@hsc.utah.edu</p>
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Department of Medicine/Nephrology and VA Medical Center, University of Utah, USA



Correspondence:

 University of Utah, Department of Medicine/Nephrology and VA Medical Center, Nephrology Research Laboratory (151M), 500 Foothill Blvd, Salt Lake City, UT 84148, USA 


E-mail: Florian.Toegel@hsc.utah.edu or Christof.Westenfelder@hsc.utah.edu
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                    [TEXT] => <p class="bodytext">Cell therapy has become a promising new treatment approach for a large number of different diseases, and applications are continually being developed. Bone marrow derived stem cells are currently being tested in clinical trials and have been shown to be promising new therapeutic vehicles. Multipotent marrow stromal cells (MSCs) are a bone marrow derived cell type that can be easily cultured and expanded in vitro and have a broad range of potential and actual therapeutic applications. The mechanism of action of MSCs in the therapeutic situation depends on the disease, and involves differentiation, immunomodulation, paracrine, and anti-apoptotic mechanisms. These mechanisms are discussed in detail in this manuscript. 
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Cell therapy has become a promising new treatment approach for a large number of different diseases, and applications are continually being developed. Bone marrow derived stem cells are currently being tested in clinical trials and have been shown to be promising new therapeutic vehicles. Multipotent marrow stromal cells (MSCs) are a bone marrow derived cell type that can be easily cultured and expanded in vitro and have a broad range of potential and actual therapeutic applications. The mechanism of action of MSCs in the therapeutic situation depends on the disease, and involves differentiation, immunomodulation, paracrine, and anti-apoptotic mechanisms. These mechanisms are discussed in detail in this manuscript. 

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