Muraca M, Galbiati G, Vilei MT, Coelho FAS, Caruso M

Language: English
References: 131
Page: 68-76
PDF size: 118.97 Kb.

Text Extraction

Preliminary experience with clinical hepatocyte transplantation during the past decade has provided proof of concept that cell therapy can be effective for the treatment of some liver diseases. Recent progress in cell biology resulting in the isolation and characterization of hepatic stem cells and progenitor cells further increased the expectation for a new approach to the treatment of genetic and chronic liver disease. Several potential sources have been identified of hepatic stem/progenitor cells exhibiting both differentiation towards the hepatic lineage in vitro and hepatic parenchymal repopulation with liver-specific metabolic activity in liver-injured animal models. However, a few of these results proved to be poorly reproducible in different laboratories, and it was recognized that some initial optimistic conclusions were drawn from incorrect interpretation of experimental data or from insufficient knowledge of the mechanisms involved in tissue regeneration. Moreover, only modest results have emerged so far from ongoing clinical experience involving the use of putative stem cells in liver disease. There is much need for a joined effort to concentrate the resources on a specific cell population, in order to better characterize its function, to assess its safety and to develop better focused clinical trials. In conclusion, while the biological features of stem cells still justify the hope for future clinical applications, hepatic stem cell therapy has still a long way to go from bench to bedside.

REFERENCES

1. Sipe JD. Tissue Engineering and Reparative Medicine. In: Sipe JD, Kelley CA, McNicol LA, eds. Reparative Medicine: Growing Tissues and Organs. Volume 961, Annals of the New York Academy of Sciences, 2002: 1-9.

2. Lake JR. Hepatocyte transplantation. N Engl J Med 1998; 338: 1463-5.

3. Gupta S, Bhargava KK, Novikoff PM. Mechanisms of cell engraftment during liver repopulation with hepatocyte transplantation. Semin Liver Dis 1999; 19: 15-26.

4. Strom SC, Chowdhury JR, Fox IJ. Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis 1999: 39-48.

5. Grompe M. Liver repopulation for the treatment of metabolic diseases. J Inherit Metab Dis 2001; 24: 231-44.

6. Horslen SP, Fox IJ. Hepatocyte transplantation. Transplantation 2004; 77: 1481-6.

7. Muraca M, Neri D, Parenti A, Feltracco P, Granato A, Vilei MT, Ferraresso C, et al. Intraportal hepatocyte transplantation in the pig. A hemodynamic and histopathological study. Transplantation 2002; 73: 890-6.

8. Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 1998; 338: 1422-6.

9. Strom SC, Fisher RA, Thompson MT, Sanyal AJ, Cole PE, Ham JM, Posner MP. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation 1997; 63: 559-69.

10. Muraca M, Gerunda G, Neri D, Vilei MT, Granato A, Feltracco P, Meroni M, et al. Hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet 2002; 359: 1528.

11. Strom SC, Rubinstein WS, Barranger JA, Towbin RB, Charron M, Mieles L, Pisarov LA, et al. Transplantation of human hepatocytes. Transplantation Proc 1997; 29: 2103-6.

12. Mitry RR, Dhawan A, Hughes RD, Bansal S, Lehec S, Terry C, Heaton ND, et al. One liver, three recipients: segment IV from split-liver procedures as a source of hepatocytes for cell transplantation. Transplantation 2004; 77: 1614-6.

13. Dhawan A, Mitry RR, Hughes RD, Lehec S, Terry C, Bansal S, Arya R, et al. Hepatocyte transplantation for inherited factor VII deficiency. Transplantation 2004; 78: 1812-4.

14. Bilir BM, Guinette D, Karrer F, Kumpe DA, Krysl J, Stephens J, et al. Hepatocyte transplantation in acute liver failure. Liver Transpl 2000; 6: 41-3.

15. Stephenne X, Najimi M, Sibille C, Nassogne MC, Smets F, Sokal EM. Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency. Gastroenterology 2006; 130: 1317-23.

16. Rosenthal N. Prometheus’s vulture and the stem-cell promise. N Engl J Med 2003; 349: 267-74.

17. Weissman IL. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 2000; 287: 1442-6.

18. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282: 1145-7.

19. Korbling M, Estrov Z. Adult stem cells for tissue repair - a new therapeutic concept? N Engl J Med 2003; 349: 570-82.

20. Laurson J, Selden C, Hodgson HJF. Hepatocyte progenitors in man and in rodents-multiple pathways, multiple candidates. Int J Path 2005; 86: 1-18.

21. Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F. Muscle regeneration by bone marrowderived myogenic progenitors. Science 1998; 279: 1528-30.

22. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, et al. Bone marrow as potential source of hepatic oval cells. Science 1999; 284: 1168-70.

23. Jackson KA, Mi T, Goodell MA. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci USA 1999; 96: 14482-6.

24. Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 1999: 283.

25. Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosi Res 2000; 61: 364-70.

26. Mezey E, Chandross KJ. Bone marrow: a possible alternative source of cells in the adult nervous system. Eur J Pharmacol 2000; 405: 297-302.

27. Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, et al. Liver from bone marrow in humans. Hepatology 2000; 32: 11-6.

28. Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, Novelli, M, et al. Hepatocytes from non-hepatic adult stem cells. Nature 2000; 406: 257.

29. Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000; 6: 1229-34.

30. Fausto N. Liver Regeneration and Repair: Hepatocytes, Progenitor Cells, and Stem Cells. Hepatology 2004; 39: 1477-87.

31. Farber E. Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3'-methyl-4-dimethylaminoazobenzene. Cancer Res 1956; 16: 142-8.

32. Grisham JW, Hartroft WS. Morphologic identification by electron microscopy of «oval» cells in experimental hepatic degeneration. Lab Invest 1961; 10: 317-32.

33. Evarts RP, Nagy P, Nakatsukasa H, Marsden E, Thorgeirsson SS. In vivo differentiation of rat liver oval cells into hepatocytes. Cancer Res 1989; 49: 1541-7.

34. Yin L, Lynch D, Ilic Z, Sell S. Proliferation and differentiation of ductular progenitor cells and littoral cells during the regeneration of the rat liver to CCl4/2-AAF injury. Histol Histopathol 2002; 17: 65-81.

35. Roskams TA, Libbrecht L, Desmet VJ. Progenitor cells in diseased human liver. Semin Liver Dis 2003; 23: 385-96.

36. Libbrecht L, Roskams T. Hepatic progenitor cells in human liver diseases. Semin Cell Dev Biol 2002; 13: 389-96.

37. Germain L, Goyette R, Marceau N. Differential cytokeratin and alpha-fetoprotein expression in morphologically distinct epithelial cells emerging at the early stage of rat hepatocarcinogenesis. Cancer Res 1985; 45: 673-81.

38. Hixson DC, Faris RA, Yang L, Novikoff P. Antigenic clues to liver development, renewal, and carcinogenesis:a integrated model. In: Sirica, AE eds. The role of cell types in hepatocarcinogenesis, CRC Press, Boca Raton, FL. 1992: 151-182.

39. Dabeva MD, Alpini G, Hurston E, Shafritz DA. Models for hepatic progenitor cell activation. Proc Soc Exp Biol Med 1993; 204: 242-52.

40. Fausto N, Campbell JS. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev 2003; 120: 117-30.

41. Dabeva MD, Laconi E, Oren R, Petkov PM, Hurston E, Shafritz DA. Liver regeneration and alpha-fetoprotein messenger RNA expression in the retrorsine model for hepatocyte transplantation. Cancer Res 1998; 58: 5825-34.

42. Gordon GJ, Coleman WB, Hixson DC, Grisham JW. Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response. Am J Pathol 2000; 156: 607-19.

43. Vig P, Russo FP, Edwards RJ, Tadrous PJ, Wright NA, Thomas HC, Alison MR, et al. The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice. Hepatology 2006; 43: 316-24.

44. Laconi E, Sarma DS, Pani P. Transplantation of normal hepatocytes modulates the development of chronic liver lesions induced by a pyrrolizidine alkaloid, lasiocarpine. Carcinogenesis 1995; 16: 139-42.

45. Laconi E, Oren R, Mukhopadhyay DK, Hurston E, Laconi S, Pani P, Dabeva MD, et al. Long-term, near-total liver replacement by transplantation of isolated hepatocytes in rats treated with retrorsine. Am J Pathol 1998; 153: 319-29.

46. Gordon GJ, Coleman WB, Grisham JW. Temporal analysis of hepatocyte differentiation by small hepatocyte-like progenitor cells during liver regeneration in retrorsine-exposed rats. Am J Pathol 2000; 157: 771-86.

47. Avril A, Pichard V, Bralet MP, Ferry N. Mature hepatocytes are the source of small hepatocyte-like progenitor cells in the retrorsine model of liver injury. J Hepatol 2004; 41: 737-43.

48. Gordon GJ, Coleman WB, Grisham JW. Induction of cytochrome P450 enzymes in the livers of rats treated with the pyrrolizidine alkaloid retrorsine. Exp Mol Pathol 2000; 69: 17-26.

49. Mattocks AR. Chemistry ann toxicology of pyrrolizidine alkaloids. London/Orlando, FL: Academic Press, 1986.

50. Fujio K, Evarts RP, Hu Z, Marsden ER, Thorgeirsson SS. Expression of stem cell factor and its receptor, c-kit, during liver regeneration from putative stem cells in adult rat. Lab Invest 1994; 70: 511-6.

51. Kabrun N, Buhring HJ, Choi K, Ullrich A, Risau W, Keller G. Flk-1 expression defines a population of early embryonic hematopoieticprecursors. Development 1997; 124: 2039-48.

52. Omori M, Evarts RP, Omori N, Hu Z, Marsden ER, Thorgeirsson SS. Expression of alpha-fetoprotein and stem cell factor/c-kit system in bile duct ligated young rats. Hepatology 1997; 25: 1115-22.

53. Petersen BE, Goff JP, Greenberger JS, Michalopoulos GK. Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat. Hepatology 1998; 27: 433-45.

54. Petersen BE, Grossbard B, Hatch H, Pi L, Deng J, Scott EW. Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers. Hepatology 2003; 37: 632-40.

55. Craig W, Kay R, Cutler RL, Lansdorp PM. Expression of Thy-1 on human hematopoietic progenitor cells. J Exp Med 1993; 177: 1331-42.

56. Taniguchi H, Toyoshima T, Fukao K, Nakauchi H. Presence of hematopoietic stem cells in the adult liver. Nat Med 1996; 2: 198-203.

57. Wang X, Ge S, McNamara G, Hao QL, Crooks GM, Nolta JA. Albumin expressing hepatocyte like cells develop in the livers of immune deficient mice that receive transplant of highly purified human hematopietic stem cells. Blood 2003; 101: 4201-8.

58. Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003; 422: 901-4.

59. Jang YY, Collector MI, Baylin SB, Diehl AM, Sharkis SJ. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol 2004; 6: 532-9.

60. Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, Lenvik T, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 2002; 109: 1291-302.

61. Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, Chen JR, et al. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 2004; 40: 1275-84.

62. Shi XL, Qiu YD, Wu XY, Xie T, Zhu ZH, Chen LL, Li L, et al. In vitro differentiation of mouse bone marrow mononuclear cells into hepatocyte-like cells. Hepatol Res 2005; 31: 223-31.

63. Menthena A, Deb N, Oertel M, Grozdanov PN, Sandhu J, Shah S, Guha C, et al. Bone marrow progenitors are not the source of expanding oval cells in injured liver. Stem Cells 2004; 22: 1049-61.

64. Erices A, Conget P. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2000; 109: 235-42.

65. Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, Chen TH. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 2004; 103: 1669-75.

66. Broxmeyer HE, Douglas GW, Hangoc G, Cooper S, Bard J, English D, Arny M, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci USA 1989; 86: 3828-32.

67. Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, Douglas GW, Devergie A, Esperou H, et al. Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilicalcord blood from an HLA-identical sibling. N Engl J Med 1989; 321: 1174-8.

68. Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC, Ciocci G, et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 1996; 335: 157-66.

69. Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337: 373-81.

70. Wagner JE, Kernan NA, Steinbuch M, Broxmeyer HE, Gluckman E. Allogeneic sibling umbilical-cord-blood transplantation in children with malignant and non-malignant disease. Lancet 1995; 346: 214-9.

71. Garbuzova-Davis S, Willing AE, Zigova T, Saporta S, Justen EB, Lane JC, Hudson JE, Chen N, Davis CD, Sanberg PR. Intravenous administration of human umbilical cord blood cells in a mouse model of amyotrophic lateral sclerosis: distribution, migration, and differentiation. J Hematother Stem Cell Res 2003; 12: 255-70.

72. Smith S, Broxmeyer HE. The influence of oxygen tension on the long-term growth in vitro of haematopoietic progenitor cells from human cord blood. Br J Haematol 1986; 63: 29-34.

73. Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation. Exp Hematol 2000; 28: 1197-205.

74. Salahuddin SZ, Markham PD, Ruscetti FW, Gallo RC. Long-term suspension cultures of human cord blood myeloid cells. Blood 1981; 58: 931-8.

75. Kakinuma S, Tanaka Y, Chinzei R, Watanabe M, Shimizu-Saito K, Hara Y, et al. Human umbilical cord blood as a source of transplantable hepatic progenitor cells. Stem Cells 2003; 21: 217-27.

76. Sharma AD, Cantz T, Richter R, Eckert K, Henschler R, Wilkens AJR, Arseniev L. Human cord blood stem cells generate human cytokeratin 18-negative hepatocyte-like cells in injured mouse liver. Am J Pathol 2005; 167: 555-64.

77. Newsome PN, Johannessen I, Boyle S, Dalakas E, McAulay KA, Samuel K, Rae F, et al. Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion. Gastroenterology 2003; 124: 1891-900.

78. Piscaglia AC, Di Campli C, Zocco MA, Di Gioacchino G, Novi M, Rutella S, Bonanno G, et al. Human cordonal stem cell intraperitoneal injection can represent a rescue therapy after an acute hepatic damage in immunocompetent rats. Transplant Proc 2005; 37: 2711-4.

79. Rutella S, Bonanno G, Marone M, De Ritis D, Mariotti A, Voso MT, Scambia G, et al. Identification of a novel subpopulation of human cord blood CD34-CD133-CD7-CD45+lineage- cells capable of lymphoid/NK cell differentiation after in vitro exposure to IL-15. J Immunol 2003; 171: 2977-88.

80. Di Campli C, Piscaglia AC, Pierelli L, Rutella S, Bonanno G, Alison MR, Mariotti A, et al. Human umbilical cord stem cell rescue therapy in a murine model of toxic liver injury. Dig Liver Dis 2004; 36: 603-13.

81. Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N, Liedtke S, et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 2004; 200: 123-35.

82. Ishii T, Ohsugi K, Nakamura S, Sato K, Hashimoto M, Mikoshiba K, Sakuragawa N. Gene expression of oligodendrocyte markers in human amniotic epithelial cells using neural cell-type-specific expression system. Neurosci Lett 1999; 268: 131-4.

83. Sakuragawa N, Thangavel R, Mizuguchi M, Hirasawa M, Kamo I. Expression of markers for both neuronal and glial cells in human amniotic epithelial cells. Neurosci Lett 1996; 209: 9-12.

84. Sakuragawa N, Enosawa S, Ishii T, Thangavel R, Tashiro T, Okuyama T, Suzuki S. Human amniotic epithelil cells are promising transgene carriers for allogenic cells transplantation into liver. J Hum Genet 2000; 45: 171.

85. In ‘t Anker PS, Scherjon SA, Kleijburg-van der Keur C, Noort WA, Claas FH, Willemze R, Fibbe WE, Kanhai HH. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 2003; 102: 1548-9.

86. Bailo M, Soncini M, Vertua E, Bonassi Signoroni P, Sanzone S, Lombardi G, et al. Engraftment potential of human and corion cells derived from placenta. Transplantation 2004; 78: 1439-48.

87. Libbrecht L, Desmet V, Van Damme B, Roskams T. The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J Hepatol 2000; 33: 76-84.

88. Roskams T, De Vos R, Van Eyken P, Myazaki H, Van Damme B, Desmet V. Hepatic OV-6 expression in human liver disease and rat experiments: evidence for hepatic progenitor cells in man. J Hepatol 1998; 29: 455-63.

89. Haque S, Haruna Y, Saito K, Nalesnik MA, Atillasoy E, Thung SN, Gerber MA. Identification of bipotential progenitor cells in human liver regeneration. Lab Invest 1996; 75: 699-705.

90. Roskams T, De Vos R, van den Oord JJ, Desmet V. Cells with neuroendocrine features in regenerating human liver. APMIS Suppl. 1991; 23: 32-9.

91. Gerber MA, Thung SN, Shen S, Stromeyer FW, Ishak KG. Phenotypic characterization of hepatic proliferation. Antigenic expression by proliferating epithelial cells in fetal liver, massive hepatic necrosis, and nodular transformation of the liver. Am J Pathol 1983; 110: 70-4.

92. Lowes KN, Brennan BA, Yeoh GC, Olynyk JK. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol 1999; 154: 537-41.

93. Fujita M, Furukawa H, Hattori M, Todo S, Ishida Y, Nagashima K. Sequential observation of liver cell regeneration after massive hepatic necrosis in auxiliary partial orthotopic liver transplantation. Mod Pathol 2000; 13: 152-7.

94. Ray MB, Mendenhall CL, French SW, Gartside PS. Bile duct changes in alcoholic liver disease. The Veterans Administration Cooperative Study Group. Liver 1993; 13: 36-45.

95. Roskams T, Yang SQ, Koteish A, Durnez A, DeVos R, Huang X, Achten R, et al. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol 2003; 163: 1301-11.

96. Libbrecht L, Desmet V, Van Damme B, Roskams T. Deep intralobular extension of human hepatic ‘progenitor cells’ correlates with parenchymal inflammation in chronic viral hepatitis: can ‘progenitor cells’ migrate? J Pathol 2000; 192: 373-8.

97. Xiao JC, Ruck P, Adam A, Wang TX, Kaiserling E. Small epithelial cells in human liver cirrhosis exhibit features of hepatic stemlike cells: immunohistochemical, electron microscopic and immunoelectron microscopic findings. Histopathology 2003; 42: 141-9.

98. Hsia CC, Evarts RP, Nakatsukasa H, Marsden ER, Thorgeirsson SS. Occurrence of oval-type cells in hepatitis B virus-associated human hepatocarcinogenesis. Hepatology 1992; 16: 1327-33.

99. Libbrecht L, Craninx M, Nevens F, Desmet V, Roskams T. Predictive value of liver cell dysplasia for development of hepatocellular carcinoma in patients with non-cirrhotic and cirrhotic chronic viral hepatitis. Histopathology 2001; 39: 66-73.

100. 100.Libbrecht L, De Vos R, Cassiman D, Desmet V, Aerts R, Roskams T. Hepatic progenitor cells in hepatocellular adenomas. Am J Surg Pathol 2001; 25: 1388-96.

101. 101.Roskams T. Progenitor cell involvement in cirrhotic human liver diseases: from controversy to consensus. J Hepatol 2003; 39: 431-4.

102. 102.Desmet V. Organizational principles. In: Arias I, Boyer JL, Chisari F, et al., eds. The Liver. Biology and pathobiology. 4th ed. Philadelphia: Lippincott Williams and Wilkins, 2001: 3-15.

103. 103.Roskams T. Acrobatic liver progenitor cells: mythology or truth? Abstract of the 5th meeting Gli incontri della veritŕ: la terapia delle malattie epatiche. 16-17 March 2006, Rome, Italy pags. 31-34.

104. 104.Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002; 297: 2256-9.

105. 105.Fuji H, Hirose T, Oe S, Yasuchika K, Azuma H, Fujikawa T, Nagao M, et al. Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice. J Hepatol 2002; 36: 653-9.

106. 106.Kanazawa Y, Verma IM. Little evidence of bone marrow-derived hepatocytes in the replacement of injured liver. Proc Natl Acad Sci USA 2003; 100 Suppl 1: 11850-3.

107. 107.Dahlke MH, Popp FC, Bahlmann FH, Aselmann H, Jager MD, Neipp M, Piso P, et al. Liver regeneration in a retrorsine/CCl4-induced acute liver failure model: do bone marrow-derived cells contribute? J Hepatol 2003; 39: 365-73.

108. 108.Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105: 369-77.

109. 109.Korbling M, Katz RN, Khanna A, Ruifrok AC, Rondon G, Albitar M, Champlin RE, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med 2002; 346: 738-46.

110. 110.Fogt F, Beyser KH, Poremba C, Zimmerman RL, Khettry U, Ruschoff J. Recipient-derived hepatocytes in liver transplants: a rare event in sex-mismatched transplants. Hepatology 2002; 36: 173-6.

111. 111.Wu T, Cieply K, Nalesnik MA, Randhawa PS, Sonzogni A, Bellamy C, Abu-Elmagd K, et al. Minimal evidence of transdifferentiation from recipient bone marrow to parenchymal cells in regenerating and long-surviving human allografts. Am J Transplant 2003; 3: 173-81.

112. 112.Ng IO, Chan KL, Shek WH, Lee JM, Fong DY, Lo CM, Fan ST. High frequency of chimerism in transplanted livers. Hepatology 2003; 38: 89-98.

113. 113.Kleeberger W, Rothamel T, Glockner S, Flemming P, Lehmann U, Kreipe H. High frequency of epithelial chimerism in liver transplants demonstrated by microdissection and STR-analysis. Hepatology 2002; 35: 10-6.

114. 114.Quintana-Bustamante O, Alvarez-Barrientos A, Kofman AV, Fabregat I, Bueren JA, Theise ND, Segovia JC. Hematopoietic mobilization in mice increases the presence of bone marrowderived hepatocytes via in vivo cell fusion. Hepatology 2006; 43: 108-16.

115. 115.Brenner DA, Waterboer T, Choi SK, Lindquist JN, Stefanovic B, Burchardt E, Yamauchi M, et al. New aspects of hepatic fibrosis. J Hepatol 2000; 32: 32-8.

116. 116.Granato A, Forbes S, Poulsom R, Muraca M, Quarta M, Rugge M, Alison M. The repopulation of liver allografts with recipient BM derived liver cells varies with time and between recipients. J Hepatol 2002; 36: 19 Abstract.

117. 117.Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, Alison MR. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004; 126: 955-63.

118. 118.Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, Okita K. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology 2004; 40: 1304-11.

119. 119.Lapidot T, Petit I. Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol 2002; 30: 973-81.

120. 120.Hatch HM, Zheng D, Jorgensen ML, Petersen BE. SDF-1alpha/CXCR4: a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats. Cloning Stem Cells 2002; 4: 339-51.

121. 121.Kollet O, Shivtiel S, Chen YQ, Suriawinata J, Thung SN, Dabeva MD, Kahn J, et al. HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J Clin Invest 2003; 112: 160-9.

122. 122.Dalakas E, Newsome PN, Harrison DJ, Plevris JN. Hematopoietic stem cell trafficking in liver injury. FASEB J 2005; 19: 1225-31.

123. 123.Kucia M, Ratajczak J, Ratajczak MZ. Are bone marrow stem cells plastic or heterogenous—that is the question. Exp Hematol 2005; 33: 613-23.

124. 124.Rolando N, Clapperton M, Wade J, Panetsos G, Mufti G, Williams R. Granulocyte colony-stimulating factor improves function of neutrophils from patients with acute liver failure. Eur J Gastroenterol Hepatol 2000; 12: 1135-40.

125. 125.Rolando N, Clapperton M, Wade J, Wendon J. Administering granulocyte colony-stimulating factor to acute liver failure patients corrects neutrophil defects. Eur J Gastroenterol Hepatol 2000; 12: 1323-8.

126. 126.Orlic D, Kajstura J, Cimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, et al. Mobilized bone marrow cells repair the infracted heart, improving function and survival. Proc Natl Acad Sci USA 2001; 98: 10344-9.

127. 127.Yannaki E, Athanasiou E, Xagorari A, Constantinou V, Batsis I, Kaloyannidis P, Proya E, 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 Hematol 2005; 33: 108-19.

128. 128.am Esch JS 2nd, Knoefel WT, Klein M, Ghodsizad A, Fuerst G, Poll LW, Piechaczek C, et al. Portal application of autologous CD133+ bone marrow cells to the liver: a novel concept to support hepatic regeneration. Stem Cells 2005; 23: 463-70.

129. 129.Avital I, Feraresso C, Aoki T, Hui T, Rozga J, Demetriou A, Muraca M. Bone marrow-derived liver stem cell and mature hepatocyte engraftment in livers undergoing rejection. Surgery 2002; 132: 384-90.

130. 130.Avital I, Inderbitzin D, Aoki T, Tyan DB, Cohen AH, Feraresso C, Rozga J, et al. Isolation, characterization, and transplantation of bone marrow-derived hepatocyte stem cells. Biochem Biophys Res Commun 2001; 288:156-64.

131. 131.Ferraresso C, Granato A, Vilei MT, Quarta M, Cozzi E, Lanza C. Ruge M, et al. Bone Marrow-derived hepatic stem cells (BMSC) repopulate rat livers after the induction of ischemia/reperfusion injury and are able to correct a congenital methabolic disorder. Abstract of the 40th Annual Meeting of the European Association for the study of the liver, April 13-17, 2005, Paris, France, pag. 260.