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• W2150640796 abstract "Morbidity and mortality from cirrhosis is increasing rapidly in the Western world. Currently the only effective treatment is liver transplantation, an increasingly limited and expensive resource. Consequently, there has been great hope that stem cells may offer new therapeutic approaches in the management of liver disease. In this review we critically appraise the 11 published clinical studies of bone marrow stem cells in liver disease, and focus on the unresolved issues regarding their role. We outline the different mechanisms by which stem cells may impact on liver disease, as well as highlight the importance of the type of stem cell chosen. There are multiple different stem cell populations that have, in rodent studies, been shown to have differing effects on liver regeneration and fibrogenesis/degradation. Thus, choice of cell should reflect the desired or expected mechanism of action. The importance, and methods, of studying the fate of stem cells infused in clinical studies is emphasized as we seek to translate observations in rodents into the clinical setting. Finally, we discuss which cohorts of patients with liver disease would benefit from stem cell therapy, as well as establish minimum criteria for future clinical trials of stem cells. Morbidity and mortality from cirrhosis is increasing rapidly in the Western world. Currently the only effective treatment is liver transplantation, an increasingly limited and expensive resource. Consequently, there has been great hope that stem cells may offer new therapeutic approaches in the management of liver disease. In this review we critically appraise the 11 published clinical studies of bone marrow stem cells in liver disease, and focus on the unresolved issues regarding their role. We outline the different mechanisms by which stem cells may impact on liver disease, as well as highlight the importance of the type of stem cell chosen. There are multiple different stem cell populations that have, in rodent studies, been shown to have differing effects on liver regeneration and fibrogenesis/degradation. Thus, choice of cell should reflect the desired or expected mechanism of action. The importance, and methods, of studying the fate of stem cells infused in clinical studies is emphasized as we seek to translate observations in rodents into the clinical setting. Finally, we discuss which cohorts of patients with liver disease would benefit from stem cell therapy, as well as establish minimum criteria for future clinical trials of stem cells. Cirrhosis and its related morbidity place a significant burden on health care worldwide. Although liver transplantation is a life-saving treatment for patients with end-stage liver disease, it has become an increasingly scarce resource, culminating in a significant increase in deaths on transplant waiting lists. Furthermore, transplantation comes with a requirement for lifelong immunosuppression, and considerable long-term side effects that include chronic renal failure, posttransplant lymphoproliferative disease, and cardiovascular complications. The search for new therapies has been actively pursued for several decades, primarily in the form of artificial liver support devices and hepatocyte transplantation, yet both of these modalities remain experimental. More recently, reports of unexpected plasticity in adult bone marrow1Petersen B.E. Bowen W.C. Patrene K.D. et al.Bone marrow as a potential source of hepatic oval cells.Science. 1999; 284: 1168-1170Google Scholar have raised hopes that stem cell therapy may offer exciting therapeutic possibilities for patients with chronic liver disease.Stem cells may be defined as cells that are clonogenic, self-renewing, and capable of differentiating into multiple cell lineages.2Weissman I.L. Stem cells: units of development, units of regeneration and units in evolution.Cell. 2000; 100: 157-168Google Scholar Stem cells may be divided into 4 different groups according to their potential for differentiation: totipotent, pluripotent, multipotent, or unipotent. The earliest embryonic stem cells are totipotent, from which the trophoblast and all 3 germ layers (endoderm, mesoderm, and ectoderm) necessary for future development of an organism are derived. Pluripotent cells contribute to all 3 germ layers. Stem cells that give rise to different lineages within a single germ layer are considered multipotent and constitute the adult stem cell population in later life. These cells are tissue-specific cells, and are capable of maintaining, generating, and replacing aging or damaged cells within the organ.3Blau H.M. Brazelton T.R. Weimann J.M. The evolving concept of a stem cell: entity or function?.Cell. 2001; 105: 829-841Google Scholar During tissue injury, it has been suggested that bone marrow stem cells are mobilized and migrate to the injured organ to maintain physiologic hemostasis.4Korbling M. Estrov Z. Adult stem cells for tissue repair—a new therapeutic concept?.N Engl J Med. 2003; 349: 570-582Google Scholar, 5Orlic D. Adult bone marrow cells regenerate myocardium in ischemic heart disease.Ann N Y Acad Sci. 2003; 996: 152-157Google Scholar This theory has formed the basis for regenerative therapy whereby treatment with appropriate stem cells might ameliorate specific diseases.Before considering the role of adjunctive stem cell therapy it is necessary to consider that the liver already contains 2 endogenous populations of stem cells in hepatocytes and hepatic oval cells. Hepatocytes fulfill many of the definitions of a stem cell in that they are able to self-renew almost limitlessly, and often play the principal role in liver regeneration.6Overturf K. Al-Dhalimy M. Ou C.N. et al.Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes.Am J Pathol. 1997; 151: 1273-1280Google Scholar, 7Rhim J.A. Sandgren E.P. Degen J.L. et al.Replacement of diseased mouse liver by hepatic cell transplantation.Science. 1994; 263: 1149-1152Google Scholar Nevertheless, this replenishment would appear to be compromised in chronic liver disease,8Wiemann S.U. Satyanarayana A. Tsahuridu M. et al.Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis.FASEB J. 2002; 16: 935-942Google Scholar, 9Murphy F. Iredale J. The telomere hypothesis for progressive liver cirrhosis.J Hepatol. 2003; 38: 378-379Google Scholar and in experimental models in which hepatocyte proliferation is restricted the contribution of hepatic oval cells has been well described.10Braun K.M. Sandgren E.P. Cellular origin of regenerating parenchyma in a mouse model of severe hepatic injury.Am J Pathol. 2000; 157: 561-569Google Scholar, 11Newsome P.N. Hussain M.A. Theise N.D. Hepatic oval cells: helping redefine a paradigm in stem cell biology.Curr Top Dev Biol. 2004; 61: 1-128Google Scholar Under conditions such as partial hepatectomy (which provides a stimulus for hepatic regeneration) and 2-AAF (2-acetyl-aminofluorene) administration (which inhibits mature hepatocyte proliferation), hepatic oval cells have been shown to differentiate into hepatocytes and cholangiocytes, leading to the restoration of hepatic volume.12Petersen B.E. Zajac V.F. Michalopoulos G.K. Hepatic oval cell activation in response to injury following chemically induced periportal or pericentral damage in rats.Hepatology. 1998; 27: 1030-1038Google Scholar, 13Gordon G.J. Coleman W.B. Hixson D.C. et al.Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response.Am J Pathol. 2000; 156: 607-619Google Scholar The origin of this cell population remains controversial, with some groups suggesting that it may in part arise from bone-marrow–derived stem cells,1Petersen B.E. Bowen W.C. Patrene K.D. et al.Bone marrow as a potential source of hepatic oval cells.Science. 1999; 284: 1168-1170Google Scholar, 14Oh S.H. Witek R.P. Bae S.H. et al.Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration.Gastroenterology. 2007; 132: 1077-1087Abstract Full Text Full Text PDF Scopus (145) Google Scholar, 15Wulf G.G. Luo K.L. Jackson K.A. et al.Cells of the hepatic side population contribute to liver regeneration and can be replenished with bone marrow stem cells.Haematologica. 2003; 88: 368-378Google Scholar although this has been challenged.16Wang X. Foster M. Al-Dhalimy M. et al.The origin and liver repopulating capacity of murine oval cells.Proc Natl Acad Sci U S A. 2003; 100: 11881-11888Google Scholar, 17Menthena A. Deb N. Oertel M. et al.Bone marrow progenitors are not the source of expanding oval cells in injured liver.Stem Cells. 2004; 22: 1049-1061Google Scholar A blood/bone-marrow–derived contribution to hepatocytes has been observed in rodents and human beings using Y chromosome tracking, in which Y+ hepatocytes were seen in the livers of male recipients of female orthotopic liver transplants (suggesting they were derived from endogenous male bone marrow), and in females who had received bone marrow transplantation from male donors.18Newsome P.N. Johannessen I. Boyle S. et al.Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion.Gastroenterology. 2003; 124: 1891-1900Google Scholar, 19Theise N.D. Nimmakayalu M. Gardner R. et al.Liver from bone marrow in humans.Hepatology. 2000; 32: 11-16Google Scholar, 20Korbling M. Katz R.L. Khanna A. et al.Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells.N Engl J Med. 2002; 346: 738-746Google Scholar, 21Alison M.R. Poulsom R. Jeffery R. et al.Hepatocytes from non-hepatic adult stem cells.Nature. 2000; 406: 257Google Scholar, 22Theise N.D. Badve S. Saxena R. et al.Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloblation.Hepatology. 2000; 31: 235-240Google Scholar, 23Krause D.S. Theise N.D. Collector M.I. et al.Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell.Cell. 2001; 105: 369-377Google Scholar, 24Avital I. Inderbitzin D. Aoki T. et al.Isolation, characterisation and transplantation of bone marrow-derived hepatocyte stem cells.Biochem Biophys Res Commun. 2001; 288: 156-164Google Scholar, 25Mallet V.O. Mitchell C. Mezey E. et al.Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo.Hepatology. 2002; 35: 799-804Google Scholar A functional contribution of bone marrow stem cells (BMSCs) to liver regeneration was shown after their transplantation into the fumarylacetoacetate hydrolase (FAH−/−) mouse whereupon they produced FAH-expressing fusion hepatocytes,26Lagasse E. Connors H. Al-Dhalimy M. et al.Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.Nat Med. 2000; 6: 1229-1234Google Scholar, 27Vassilopoulos G. Wang P.R. Russell D.W. Transplanted bone marrow regenerates liver by cell fusion.Nature. 2003; 422: 901-904Google Scholar, 28Wang X. Willenbring H. Akkari Y. et al.Cell fusion is the principal source of bone-marrow-derived hepatocytes.Nature. 2003; 422: 897-901Google Scholar and led to an improvement in liver function and survival. The FAH−/− mouse develops liver failure as a result of tyrosinemia, and ordinarily is kept alive only by the administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione. BMSC plasticity has been suggested for a number of different tissue types,29Ferrari G. Cusella-De Angelis G. Coletta M. et al.Muscle regeneration by bone marrow-derived myogenic progenitors.Science. 1998; 279: 1528-1530Google Scholar, 30Orlic D. Kajstura J. Chimenti S. et al.Bone marrow cells regenerate infracted myocardium.Nature. 2001; 410: 701-705Google Scholar and has generated hope of its use as a cellular therapy for a variety of diseases. This initial optimism has been tempered by a recognition that much of the observed plasticity occurred at either a low level or was the consequence of cellular fusion (of bone marrow with tissue-specific cells).28Wang X. Willenbring H. Akkari Y. et al.Cell fusion is the principal source of bone-marrow-derived hepatocytes.Nature. 2003; 422: 897-901Google Scholar, 31Quintana-Bustamante O. Alvarez-Barrientos A. Kofman A.V. et al.Hematopoietic mobilisation in mice increases the presence of bone marrow-derived hepatocytes via in vivo cell fusion.Hepatology. 2006; 43: 108-116Google ScholarAlthough initial attention focused on the contribution of bone marrow cells to hepatocytes, several groups identified that they made a potentially more significant contribution to other tissue-based cells, such as macrophages and myofibroblasts, which were responsible for the production of scar tissue.32Takezawa R. Watanabe Y. Akaike T. Direct evidence of macrophage differentiation from bone marrow cells in the liver: a possible origin of Kupffer cells.J Biochem (Tokyo). 1995; 118: 1175-1183Crossref Scopus (43) Google Scholar, 33Russo F.P. Alison M.R. Bigger B.W. et al.The bone marrow functionally contributes to liver fibrosis.Gastroenterology. 2006; 130: 1807-1821Abstract Full Text Full Text PDF Scopus (434) Google Scholar, 34Kisseleva T. Uchinami H. Feirt N. et al.Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis.J Hepatol. 2006; 45: 429-438Google Scholar This observation, in both rodents and human beings, raised the possibility that a bone marrow contribution may not be entirely beneficial, and indeed may be harmful. Paradoxically, rodent studies reported that infusion of bone marrow during chronic liver injury reduced the amount of fibrosis seen, an effect possibly mediated by the observation of increased numbers of bone marrow–derived matrix metalloproteinase-9–expressing cells juxtaposed to areas of fibrosis.35Sakaida I. Terai S. Yamamoto N. et al.Transplantation of bone marrow cells reduces CCL4-induced liver fibrosis in mice.Hepatology. 2004; 40: 1304-1311Google Scholar, 36Fang B. Shi M. Liao L. et al.Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice.Transplantation. 2004; 78: 83-88Google Scholar, 37Zhao D.C. Lei J.X. Chen R. et al.Bone marrow derived mesenchymal stem cells protect against experimental liver fibrosis in rats.World J Gastroenterol. 2005; 11: 3431-3440Google Scholar, 38Oyagi S. Hirose M. Kojima M. et al.Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats.J Hepatol. 2006; 44: 742-748Google Scholar Although many unresolved issues remain in this field several groups have proceeded to clinical studies with stem cells in patients with chronic liver disease.To date, there are 11 published human clinical studies investigating the effects of BMSC therapy in patients with liver disease.39Gaia S. Smedile A. Omede P. et al.Feasibility and safety of G-CSF administration to induce bone marrow-derived cells mobilization in patients with end stage liver disease.J Hepatol. 2006; 45: 13-19Google Scholar, 40Terai S. Ishikawa T. Omori K. et al.Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy.Stem Cells. 2006; 24: 2292-2298Google Scholar, 41Mohamadnejad M. Namiri M. Bagheri M. et al.Phase 1 human trial of autologous bone marrow-hematopoietic stem cell transplantation in patients with decompensated cirrhosis.World J Gastroenterol. 2007; 28: 3359-3363Google Scholar, 42Mohamadnejad M. Alimoghaddam K. Mohyeddin-Bonab M. et al.Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis.Arch Iran Med. 2007; 10: 459-466Google Scholar, 43Lyra A.C. Soares M.B. da Silva L.F. et al.Feasibility and safety of autologous bone marrow mononuclear cell transplantation in patients with advanced chronic liver disease.World J Gastroenterol. 2007; 13: 1067-1073Google Scholar, 44Lyra A.C. Soares M.B. da Silva L.F. et al.A pilot randomised controlled study used to evaluate efficacy of autologous bone marrow mononuclear cells transplantation in patients with advanced chronic liver disease.Hepatology. 2007; 46 (abstr): 271AGoogle Scholar, 45Gordon M.Y. Levicar N. Pai M. et al.Characterisation and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor.Stem Cells. 2006; 24: 1822-1830Google Scholar, 46Levicar N. Pai M. Habib N.A. et al.Long-term clinical results of autologous infusion of mobilized adult bone marrow derived CD34+ cells in patients with chronic liver disease.Cell Prolif. 2008; 41: 115-125Google Scholar, 47Yannaki E. Anagnostopoulos A. Kapetanos D. et al.Lasting amelioration in the clinical course of decompensated alcoholic cirrhosis with boost infusions of mobilized peripheral blood stem cells.Exp Hematol. 2006; 34: 1583-1587Google Scholar, 48am Esch 2nd, J.S. Knoefel W.T. Klein M. et al.Portal application of autologous CD133+ bone marrow cells to the liver: a novel concept to support hepatic regeneration.Stem Cells. 2005; 23: 463-470Google Scholar, 49Furst G. Schulte am Esch J. Poll L.W. et al.Portal vein embolisation and autologous CD133+ bone marrow stem cells for liver regeneration: initial experience.Radiology. 2007; 243: 171-179Google Scholar This review critically examines these studies and focuses on some of the key issues facing the use of stem cells in liver disease: defining the purpose of stem cell therapy, the choice of cell type, the tracking and phenotyping of cells after infusion, and the appropriate clinical end points of such clinical trials. However, before describing the trials in detail we examine the putative mechanisms through which stem cells may ameliorate chronic liver disease.By What Mechanism Are BMSCs Proposed to Impart Benefit?Initial studies had suggested that adult stem cell plasticity and their differentiation to hepatocytes represented their mechanism of action in liver injury (Figure 1).18Newsome P.N. Johannessen I. Boyle S. et al.Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion.Gastroenterology. 2003; 124: 1891-1900Google Scholar, 21Alison M.R. Poulsom R. Jeffery R. et al.Hepatocytes from non-hepatic adult stem cells.Nature. 2000; 406: 257Google Scholar, 22Theise N.D. Badve S. Saxena R. et al.Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloblation.Hepatology. 2000; 31: 235-240Google Scholar, 23Krause D.S. Theise N.D. Collector M.I. et al.Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell.Cell. 2001; 105: 369-377Google Scholar, 50Jang Y.Y. Collector M.I. Baylin S.B. et al.Hematopoietic stem cells convert into liver cells within days without fusion.Nat Cell Biol. 2004; 6: 532-539Google Scholar This has become a controversial issue, with many groups suggesting that fusion of adult stem cells with endogenous hepatocytes is the dominant mechanism by which new hepatocytes are produced.27Vassilopoulos G. Wang P.R. Russell D.W. Transplanted bone marrow regenerates liver by cell fusion.Nature. 2003; 422: 901-904Google Scholar, 30Orlic D. Kajstura J. Chimenti S. et al.Bone marrow cells regenerate infracted myocardium.Nature. 2001; 410: 701-705Google Scholar, 31Quintana-Bustamante O. Alvarez-Barrientos A. Kofman A.V. et al.Hematopoietic mobilisation in mice increases the presence of bone marrow-derived hepatocytes via in vivo cell fusion.Hepatology. 2006; 43: 108-116Google Scholar More importantly, however, is the recognition that irrespective of the mechanism, the number of hepatocytes produced is very low in the vast majority of situations and is thus unlikely to impact clinically at present. It is in situations in which the stem cell progeny, whether it be by fusion or differentiation, have a survival advantage that large numbers of such cells are seen. Indeed, in the FAH−/− model of tyrosinemia, infusion of wild-type hematopoietic stem cells (HSCs) into this mouse led to correction of the metabolic defect and survival of the animal.26Lagasse E. Connors H. Al-Dhalimy M. et al.Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.Nat Med. 2000; 6: 1229-1234Google Scholar This has implications for the design of clinical studies because it may require either nonautologous infusions (for metabolic liver disease) or ex vivo manipulation of cells such that they are resistant to viral entry/damage (hepatitis B/C).The concept of stem cell infusions exerting a paracrine proliferative effect on endogenous hepatocytes is gaining support, and is backed up by both rodent and human studies, although the latter are small uncontrolled studies. Endogenous hepatocytes in cirrhotic livers are reported to have reduced proliferative capacity, which may reflect either the inhibitory effect of adjacent collagen I, or that they have reached replicative senescence after many rounds of injury and repair.4Korbling M. Estrov Z. Adult stem cells for tissue repair—a new therapeutic concept?.N Engl J Med. 2003; 349: 570-582Google Scholar, 5Orlic D. Adult bone marrow cells regenerate myocardium in ischemic heart disease.Ann N Y Acad Sci. 2003; 996: 152-157Google Scholar, 51Fassett J.T. Tolbot D. Nelsen C.J. et al.The role of collagen structure in mitogen stimulation of ERK, cyclin D1 expression, and G1-S progression in rat hepatocytes.J Biol Chem. 2003; 278: 31691-31700Google Scholar, 52Fassett J. Tolbot D. Hansen L.K. Type I collagen structure regulates cell morphology and EGF signalling in primary rat hepatocytes through cAMP-dependant protein kinase A.Mol Biol Cell. 2006; 17: 345-356Google Scholar, 53Trak-Smayra V. Contreras J. Dondero F. et al.Role of replicative senescence in the progression of fibrosis in hepatitis C virus (HCV) recurrence after liver transplantation.Transplantation. 2004; 77: 1755-1760Google Scholar Stem cell infusion may increase the intrinsic ability of hepatocytes to proliferate by release of proliferative cytokines, or by facilitating the breakdown of scar tissue, thereby removing a block to proliferation. Other cell populations such as endothelial precursor cells have been shown in rodent models to promote angiogenesis and the degradation of liver scar tissue.54Taniguchi E. Kin M. Torimura T. et al.Endothelial progenitor cell transplantation improves the survival following liver injury in mice.Gastroenterology. 2006; 130: 521-531Google Scholar, 55Nakamura T. Torimura T. Sakamoto M. et al.Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model.Gastroenterology. 2007; 133: 91-107Abstract Full Text Full Text PDF Scopus (129) Google Scholar, 56Ueno T. Nakamura T. Torimura T. et al.Angiogenic cell therapy for hepatic fibrosis.Med Mol Morphol. 2006; 39: 16-21Google Scholar This has yet to be confirmed in clinical studies.Rather than focusing on the production of hepatocytes, other groups have examined the effect of stem cells on remodeling the fibrosis seen in end-stage liver disease. Although synthetic failure is part of the clinical picture of liver disease, many of the clinical manifestations reflect fibrosis and subsequent portal hypertension. Rodent studies have shown that infusion of bone marrow during liver injury reduces the amount of liver scarring, with a suggestion that this may be owing to matrix metalloproteinase-9 expression of bone marrow–derived cells.35Sakaida I. Terai S. Yamamoto N. et al.Transplantation of bone marrow cells reduces CCL4-induced liver fibrosis in mice.Hepatology. 2004; 40: 1304-1311Google Scholar, 36Fang B. Shi M. Liao L. et al.Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice.Transplantation. 2004; 78: 83-88Google Scholar, 37Zhao D.C. Lei J.X. Chen R. et al.Bone marrow derived mesenchymal stem cells protect against experimental liver fibrosis in rats.World J Gastroenterol. 2005; 11: 3431-3440Google Scholar, 38Oyagi S. Hirose M. Kojima M. et al.Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats.J Hepatol. 2006; 44: 742-748Google Scholar, 57Payne C. Samuel K. Pryde A. et al.The impact of bone marrow stem cells on liver fibrosis in critically determined by their route of cell trafficking.Hepatology. 2007; 46: 710AGoogle Scholar This effect needs to be reproduced in different types of liver injury, and more importantly, shown in human liver disease. Nevertheless, if confirmed this will form a major part of our antifibrotic strategy.Stem Cell Subtypes and Differential Effects Within the LiverThere are 2 major types of adult stem cell: HSCs and mesenchymal stem cells (MSCs), both of which are found predominantly in the bone marrow, although the latter can be found in adipose tissue in reasonable numbers.58Banas A. Teratani T. Yamamoto Y. et al.Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes.Hepatology. 2007; 46: 219-228Google Scholar HSCs have been well characterized with respect to their recapitulation of the major hematopoietic lineages, and cell surface markers that can be used to identify, and isolate, them. In human beings, expression of CD34 on the cell surface is largely used in clinical practice, although CD133 expression is believed to represent a more stem cell–enriched subpopulation of the CD34+ cells.59Wynter E.A. Buck D. Hart C. et al.CD34+AC133+ cells isolated from cord blood are highly enriched in long-term culture-initiating cells, NOD/SCID-repopulating cells and dendritic cell progenitors.Stem Cells. 1998; 16: 387-396Google Scholar The expression of these markers does not denote that these cells are stem cells; rather it implies that the population is enriched for stem cells. True pluripotent stem cells would constitute about 0.1% of a CD133+ population.60Kucia M. Reca R. Campbell F.R. et al.A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1Oct-4(+) stem cells identified in adult bone marrow.Leukemia. 2006; 20: 857-869Google Scholar, 61Kucia M. Halasa M. Wysoczynski M. et al.Morphological and molecular characterisation of novel population of CXCR4+ SSEA-4+ Oct-4+ very small embryonic-like cells purified from human cord blood: preliminary report.Leukemia. 2007; 21: 297-303Google Scholar MSCs are more difficult to define, and cell surface expression is not used routinely to isolate them, and subsequently their ability to adhere to plastic and differentiate down chondrocytic and adipocytic lineages is largely used to confirm their identity.62Dominici M. Le Blanc K. Mueller I. et al.Minimal criteria for defining multipotent mesenchymal stromal cells The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317Google Scholar As such, they comprise a fairly heterogeneous population.63Wagner W. Ho A.D. Mesenchymal stem cell preparations-comparing apples and oranges.Stem Cell Rev. 2007; 3: 239-248Google Scholar Thus, although MSCs may offer exciting therapeutic possibilities there are significant issues to be overcome in terms of defining and isolating a more homogeneous population of cells. More recently, a novel stem cell (tooth germ progenitor cell) has been isolated from the human third molar tooth.64Ikeda E. Yagi K. Kojima M. et al.Multipotent cells from the human third molar: feasibility of cell-based therapy for liver disease.Differentiation. 2008; 76: 495-505Google Scholar Transplantation of this cell type into a rodent model of liver injury (carbon tetrachloride induced), appeared to prevent liver fibrosis, and ameliorate liver function. Further trials will be required to verify these effects and elucidate their mechanism of action within the injured liver.The choice of stem cell in human clinical trials will reflect, in part, the investigator's believed mechanism of action. These mechanisms include transdifferentiation, stimulation of endogenous hepatocyte proliferation, and antifibrotic and immunomodulatory effects. If they believe plasticity is the major mechanism, then there is literature supporting both HSCs and MSCs, although it is probably more compelling for MSCs. Many of the initial studies suggested that HSCs were the predominant cell type involved,26Lagasse E. Connors H. Al-Dhalimy M. et al.Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.Nat Med. 2000; 6: 1229-1234Google Scholar but more recently in vitro and in vivo experiments have supported transdifferentiation of MSCs into hepatocytes.65Tamagawa T. Oi S. Ishiwata I. et al.Differentiation of mesenchymal cells derived from human amniotic membranes into hepatocyte-like cells in vitro.Hum Cell. 2007; 20: 77-84Google Scholar, 66Najimi M. Khuu D.N. Lysy P.A. et al.Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes?.Cell Transplant. 2007; 16: 717-728Google Scholar, 67Sato Y. Araki H. Kato J. et al.Human mesenchymal stem cells xenografted directly to rat are differentiated into human hepatocytes without fusion.Blood. 2005; 106: 756-763Google Scholar If stimulation of endogenous hepatocyte proliferation is desired, there is evidence to support the use of HSCs.68Piscaglia A.C. Shupe T.D. Oh S.H. et al.Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats.Gastroenterology. 2007; 133: 619-631Google Scholar, 69Yannaki E. Athanasiou E. Xagorari A. et al.G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs.Exp Haematol. 2005; 33: 108-119Google Scholar The effects of MSCs are not known in this setting. As for antifibrotic effects, the literature is less clear in that unsorted bone marrow has" @default.
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• W2150640796 date "2008-08-01" @default.
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• W2150640796 title "Critical Review of Clinical Trials of Bone Marrow Stem Cells in Liver Disease" @default.
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