Gastroenterology
Volume 135, Issue 2 , Pages 438-450 , August 2008

Critical Review of Clinical Trials of Bone Marrow Stem Cells in Liver Disease

  • Diarmaid Dominic Houlihan
  • ,
  • Philip Noel Newsome

      Affiliations

    • Corresponding Author InformationAddress reprint requests to: Phil Newsome, MD, PhD, Liver Research Group, 5th Floor, Institute of Biomedical Research, Wolfson Drive, The Medical School, Edgbaston, University of Birmingham, Birmingham B15 2TT, United Kingdom. fax: (0121) 415-8701.

Received 28 January 2008 ,Accepted 8 May 2008.

References 

  1. Petersen BE, Bowen WC, Patrene KD, et al. Bone marrow as a potential source of hepatic oval cells. Science. 1999;284:1168–1170
  2. Weissman IL. Stem cells: units of development, units of regeneration and units in evolution. Cell. 2000;100:157–168
  3. Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function?. Cell. 2001;105:829–841
  4. Korbling M, Estrov Z. Adult stem cells for tissue repair—a new therapeutic concept?. N Engl J Med. 2003;349:570–582
  5. Orlic D. Adult bone marrow cells regenerate myocardium in ischemic heart disease. Ann N Y Acad Sci. 2003;996:152–157
  6. Overturf K, Al-Dhalimy M, Ou CN, et al. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol. 1997;151:1273–1280
  7. Rhim JA, Sandgren EP, Degen JL, et al. Replacement of diseased mouse liver by hepatic cell transplantation. Science. 1994;263:1149–1152
  8. Wiemann SU, Satyanarayana A, Tsahuridu M, et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 2002;16:935–942
  9. Murphy F, Iredale J. The telomere hypothesis for progressive liver cirrhosis. J Hepatol. 2003;38:378–379
  10. Braun KM, Sandgren EP. Cellular origin of regenerating parenchyma in a mouse model of severe hepatic injury. Am J Pathol. 2000;157:561–569
  11. Newsome PN, Hussain MA, Theise ND. Hepatic oval cells: helping redefine a paradigm in stem cell biology. Curr Top Dev Biol. 2004;61:1–128
  12. Petersen BE, Zajac VF, Michalopoulos GK. Hepatic oval cell activation in response to injury following chemically induced periportal or pericentral damage in rats. Hepatology. 1998;27:1030–1038
  13. Gordon GJ, Coleman WB, Hixson DC, et al. Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response. Am J Pathol. 2000;156:607–619
  14. Oh SH, Witek RP, Bae SH, et al. Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration. Gastroenterology. 2007;132:1077–1087
  15. Wulf GG, Luo KL, Jackson KA, et al. Cells of the hepatic side population contribute to liver regeneration and can be replenished with bone marrow stem cells. Haematologica. 2003;88:368–378
  16. Wang 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;100:11881–11888
  17. Menthena A, Deb N, Oertel M, et al. Bone marrow progenitors are not the source of expanding oval cells in injured liver. Stem Cells. 2004;22:1049–1061
  18. Newsome PN, 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;124:1891–1900
  19. Theise ND, Nimmakayalu M, Gardner R, et al. Liver from bone marrow in humans. Hepatology. 2000;32:11–16
  20. Korbling M, Katz RL, Khanna A, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med. 2002;346:738–746
  21. Alison MR, Poulsom R, Jeffery R, et al. Hepatocytes from non-hepatic adult stem cells. Nature. 2000;406:257
  22. Theise ND, Badve S, Saxena R, et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloblation. Hepatology. 2000;31:235–240
  23. Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001;105:369–377
  24. Avital I, Inderbitzin D, Aoki T, et al. Isolation, characterisation and transplantation of bone marrow-derived hepatocyte stem cells. Biochem Biophys Res Commun. 2001;288:156–164
  25. Mallet VO, 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;35:799–804
  26. Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6:1229–1234
  27. Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003;422:901–904
  28. Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003;422:897–901
  29. Ferrari G, Cusella-De Angelis G, Coletta M, et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279:1528–1530
  30. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infracted myocardium. Nature. 2001;410:701–705
  31. Quintana-Bustamante O, Alvarez-Barrientos A, Kofman AV, et al. Hematopoietic mobilisation in mice increases the presence of bone marrow-derived hepatocytes via in vivo cell fusion. Hepatology. 2006;43:108–116
  32. Takezawa 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;118:1175–1183
  33. Russo FP, Alison MR, Bigger BW, et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology. 2006;130:1807–1821
  34. Kisseleva T, Uchinami H, Feirt N, et al. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol. 2006;45:429–438
  35. Sakaida I, Terai S, Yamamoto N, et al. Transplantation of bone marrow cells reduces CCL4-induced liver fibrosis in mice. Hepatology. 2004;40:1304–1311
  36. Fang B, Shi M, Liao L, et al. Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation. 2004;78:83–88
  37. Zhao DC, Lei JX, Chen R, et al. Bone marrow derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J Gastroenterol. 2005;11:3431–3440
  38. Oyagi S, Hirose M, Kojima M, et al. Therapeutic effect of transplanting HGF-treated bone marrow mesenchymal cells into CCl4-injured rats. J Hepatol. 2006;44:742–748
  39. Gaia 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;45:13–19
  40. Terai 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;24:2292–2298
  41. Mohamadnejad 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;28:3359–3363
  42. Mohamadnejad 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;10:459–466
  43. Lyra AC, Soares MB, da Silva LF, et al. Feasibility and safety of autologous bone marrow mononuclear cell transplantation in patients with advanced chronic liver disease. World J Gastroenterol. 2007;13:1067–1073
  44. Lyra AC, Soares MB, da Silva LF, 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(Suppl 1):271A;(abstr)
  45. Gordon MY, 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;24:1822–1830
  46. Levicar N, Pai M, Habib NA, 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;41:115–125
  47. Yannaki 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;34:1583–1587
  48. am Esch JS, Knoefel WT, 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;23:463–470
  49. Furst G, Schulte am Esch J, Poll LW, et al. Portal vein embolisation and autologous CD133+ bone marrow stem cells for liver regeneration: initial experience. Radiology. 2007;243:171–179
  50. Jang YY, Collector MI, Baylin SB, et al. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol. 2004;6:532–539
  51. Fassett JT, Tolbot D, Nelsen CJ, 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;278:31691–31700
  52. Fassett J, Tolbot D, Hansen LK. Type I collagen structure regulates cell morphology and EGF signalling in primary rat hepatocytes through cAMP-dependant protein kinase A. Mol Biol Cell. 2006;17:345–356
  53. Trak-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;77:1755–1760
  54. Taniguchi E, Kin M, Torimura T, et al. Endothelial progenitor cell transplantation improves the survival following liver injury in mice. Gastroenterology. 2006;130:521–531
  55. Nakamura T, Torimura T, Sakamoto M, et al. Significance and therapeutic potential of endothelial progenitor cell transplantation in a cirrhotic liver rat model. Gastroenterology. 2007;133:91–107
  56. Ueno T, Nakamura T, Torimura T, et al. Angiogenic cell therapy for hepatic fibrosis. Med Mol Morphol. 2006;39:16–21
  57. Payne 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;46:710A
  58. Banas A, Teratani T, Yamamoto Y, et al. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology. 2007;46:219–228
  59. Wynter EA, 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;16:387–396
  60. Kucia M, Reca R, Campbell FR, et al. A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1Oct-4(+) stem cells identified in adult bone marrow. Leukemia. 2006;20:857–869
  61. Kucia 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;21:297–303
  62. Dominici 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;8:315–317
  63. Wagner W, Ho AD. Mesenchymal stem cell preparations-comparing apples and oranges. Stem Cell Rev. 2007;3:239–248
  64. Ikeda E, Yagi K, Kojima M, et al. Multipotent cells from the human third molar: feasibility of cell-based therapy for liver disease. Differentiation. 2008;76:495–505
  65. Tamagawa 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;20:77–84
  66. Najimi M, Khuu DN, Lysy PA, et al. Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes?. Cell Transplant. 2007;16:717–728
  67. Sato Y, Araki H, Kato J, et al. Human mesenchymal stem cells xenografted directly to rat are differentiated into human hepatocytes without fusion. Blood. 2005;106:756–763
  68. Piscaglia AC, Shupe TD, Oh SH, et al. Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats. Gastroenterology. 2007;133:619–631
  69. Yannaki 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;33:108–119
  70. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110:3499–3506
  71. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted actions of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141–150
  72. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439–1441
  73. Prochymal Crohn's Disease Phase II Clinical Trial Data. http://www.osiris.comAccessed 29 June 2008
  74. Mazhari R, Hare JM. Advances in cell-based therapy for structural heart disease. Prog Cardiovasc Dis. 2007;49:387–395
  75. Christoforou N, Gearhart JD. Stem cells and their potential in cell-based cardiac therapies. Prog Cardiovasc Dis. 2007;49:396–413
  76. Liu F, Pan X, Chen G, et al. Hematopoietic stem cells mobilized by granulocyte colony-stimulating factor partly contribute to liver graft regeneration after partial orthotopic liver transplantation. Liver Transpl. 2006;12:1129–1137
  77. Gehling UM, Willems M, Dandri M, et al. Partial hepatectomy induces mobilization of a unique population of haematopoietic progenitor cells in human healthy liver donors. J Hepatol. 2005;43:845–853
  78. Giron-Gonzalez JA, Martinez-Sierra C, Rodriguez-Ramos C, et al. Implication of inflammation-related cytokines in the natural history of liver cirrhosis. Liver Int. 2004;24:437–445
  79. Genesca J, Gonzalez A, Segura R, et al. Interleukin-6, nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis. Am J Gastroenterol. 1999;94:169–177
  80. Yan L, Han Y, He Y, et al. Cell tracing techniques in stem cell transplantation. Stem Cell Rev. 2007;3:265–269
  81. Kiel MJ, He S, Ashkenazi R, et al. Haemopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature. 2007;449:238–242
  82. Svilvassy SJ, Meyerrose TE, Ragland PL, et al. Differential homing and engraftment properties of hematopoietic progenitor cells from murine bone marrow, mobilized peripheral blood, and fetal liver. Blood. 2001;98:2108–2115
  83. Zhan Y, Wang Y, Wei L, et al. Differentiation of hematopoietic stem cells into hepatocytes in liver fibrosis in rats. Transplantation Proc. 2006;38:3082–3085
  84. Modo M, Cash D, Mellodew K, et al. Tracking transplanted stem cell migration using bifunctional, contrast agent-enhanced, magnetic resonance imaging. Neuroimage. 2002;17:803–811
  85. Amsalem Y, Mardor Y, Feinberg MS, et al. Iron-oxide labeling and outcome of transplanted mesenchymal stem cells in the infracted myocardium. Circulation. 2007;116:I38–I145
  86. Caveliers V, De Keulenaer G, Everaert H, et al. In vivo visualisation of 111In labelled CD133+ peripheral blood stem cells after intracoronary administration in patients with chronic ischaemic heart disease. Q J Nucl Med Mol Imaging. 2007;51:61–66
  87. Gao J, Dennis JE, Muzic RF, et al. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs. 2001;169:12–20
  88. Dalakas E, Newsome PN, Harrison DJ, et al. Hematopoietic stem cell trafficking in liver injury. FASEB J. 2005;19:1225–1231
  89. Cassiman D, Barlow A, Vander Borght S, et al. Hepatic stellate cells do not derive from the neural crest. J Hepatol. 2006;44:1098–1104
  90. Wu XZ, Chen D. Origin of hepatocellular carcinoma: role of stem cells. J Gastroenterol Hepatol. 2006;21:1093–1098
  91. Dumble ML, Croager EJ, Yeoh GC, et al. Generation and characterisation of p53 null transformed hepatic progenitor cells: oval cells give rise to hepatocellular carcinoma. Carcinogenesis. 2002;23:435–445
  92. Becker R, Luthgens B, Oesch F, et al. Ha-rasVal12 but not p53ser247 leads to a significant neoplastic transformation rate of the putative rat liver stem cells (oval cell). Carcinogenesis. 1996;17:2635–2640
  93. Rubio D, Garcia-Castro J, Martín MC, et al. Spontaneous human adult stem cell transformation. Cancer Res. 2005;65:3035–3039
  94. Serakinci N, Guldberg P, Burns JS, et al. Adult human mesenchymal stem cell as a target for neoplastic transformation. Oncogene. 2004;23:5095–5098
  95. Hsieh CB, Chen CJ, Chen TW, et al. Accuracy of indocyanine green pulse spectrophotometry clearance test for liver function prediction in transplanted patients. World J Gastroenterol. 2004;15:2394–2396
  96. Horn KD, Wax P, Schneider SM, et al. Biomarkers of liver regeneration allow early prediction of hepatic recovery after acute necrosis. Am J Clin Pathol. 1999;112:351–357
  97. Assy N, Gong Y, Zhang M, et al. Use of proliferating cell nuclear antigen as a marker of liver regeneration after partial hepatectomy in rats. J Lab Clin Med. 1998;131:251–256
  98. Bockhorn M, Goralski M, Prokofiev D, et al. VEGF is important for early liver regeneration after partial hepatectomy. J Surg Res. 2007;138:291–299
  99. Streetz KL, Luedde T, Manns MP, et al. Interleukin 6 and liver regeneration. Gut. 2000;47:309–312
  100. Dinant S, Vetelainen RL, Florquin S, et al. Il-10 attenuates hepatic I/R injury and promotes hepatocyte proliferation. J Surg Res. 2007;141:176–182
  101. Campbell JS, Prichard L, Schaper F, et al. Expression of suppressors of cytokine signalling during liver regeneration. J Clin Invest. 2001;107:1285–1292
  102. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449–1457
  103. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97:2614–2618
  104. Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology. 2004;127:1704–1713
  105. Guha IN, Parkes J, Roderick PR, et al. Noninvasive markers of fibrosis in non-alcoholic fatty liver disease: validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology. 2008;47:455–460

PII: S0016-5085(08)00861-5

doi: 10.1053/j.gastro.2008.05.040

Gastroenterology
Volume 135, Issue 2 , Pages 438-450 , August 2008