• 1
    Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 2004; 39: 147787.
  • 2
    Lazaro CA, Rhim JA, Yamada Y, Fausto N. Generation of hepatocytes from oval cell precursors in culture. Cancer Res. 1998; 58: 551422.
  • 3
    Dunsford HA, Karnasuta C, Hunt JM, Sell S. Different lineages of chemically induced hepatocellular carcinoma in rats defined by monoclonal antibodies. Cancer Res. 1989; 49: 4894900.
  • 4
    Theise ND, Saxena R, Portmann BC et al. The canals of Hering and hepatic stem cells in humans. Hepatology 1999; 30: 142533.
  • 5
    Roskams T. Different types of liver progenitor cells and their niches. J. Hepatol. 2006; 45: 14.
  • 6
    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: 53741.
  • 7
    Roskams T, Yang SQ, Koteish A et al. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am. J. Pathol. 2003; 163: 130111.
  • 8
    Sakaida I. Autologous bone marrow cell infusion therapy for liver cirrhosis. J. Gastroenterol. Hepatol. 2008 (in press).
  • 9
    Laurson J, Selden C, Hodgson HJ. Hepatocyte progenitors in man and in rodents—multiple pathways, multiple candidates. Int. J. Exp Pathol 2005; 86: 118.
  • 10
    Potten CS, Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 1990; 110: 100120.
  • 11
    ISSCR. Glossary, International Society for Stem Cell Research. Northbrook, IL: USA The International Society for Stem Cell Research, 2007.
  • 12
    Overturf K, Al-Dhalimy M, Ou CN, Finegold M, Grompe M. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am. J. Pathol. 1997; 151: 127380.
  • 13
    Tateno C, Yoshizane Y, Saito N et al. Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am. J. Pathol. 2004; 165: 90112.
  • 14
    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: 60719.
  • 15
    Evarts RP, Nagy P, Marsden E, Thorgeirsson SS. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis 1987; 8: 173740.
  • 16
    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: 10308.
  • 17
    Lemire JM, Shiojiri N, Fausto N. Oval cell proliferation and the origin of small hepatocytes in liver injury induced by d-galactosamine. Am. J. Pathol. 1991; 139: 53552.
  • 18
    Shinozuka H, Lombardi B, Sell S, Iammarino RM. Early histological and functional alterations of ethionine liver carcinogenesis in rats fed a choline-deficient diet. Cancer Res. 1978; 38: 10928.
  • 19
    Akhurst B, Croager EJ, Farley-Roche CA et al. A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver. Hepatology 2001; 34: 51922.
  • 20
    Crosby HA, Kelly DA, Strain AJ. Human hepatic stem-like cells isolated using c-kit or CD34 can differentiate into biliary epithelium. Gastroenterology 2001; 120: 53444.
  • 21
    Yovchev MI, Grozdanov PN, Zhou H, Racherla H, Guha C, Dabeva MD. Identification of adult hepatic progenitor cells capable of repopulating injured rat liver. Hepatology 2008; 47: 63647.
  • 22
    Sicklick JK, Choi SS, Bustamante M et al. Evidence for epithelial-mesenchymal transitions in adult liver cells. Am. J. Physiol. Gastrointest Liver Physiol. 2006; 291: G57583.
  • 23
    Fougere-Deschatrette C, Imaizumi-Scherrer T, Strick-Marchand H et al. Plasticity of hepatic cell differentiation: bipotential adult mouse liver clonal cell lines competent to differentiate in vitro and in vivo. Stem Cells 2006; 24: 2098109.
  • 24
    Herrera MB, Bruno S, Buttiglieri S et al. Isolation and characterization of a stem cell population from adult human liver. Stem Cells 2006; 24: 284050.
  • 25
    Schmelzer E, Wauthier E, Reid LM. The phenotypes of pluripotent human hepatic progenitors. Stem Cells 2006; 24: 18528.
  • 26
    Schmelzer E, Zhang L, Bruce A et al. Human hepatic stem cells from fetal and postnatal donors. J. Exp. Med. 2007; 204: 197387.
  • 27
    Germain L, Blouin MJ, Marceau N. Biliary epithelial and hepatocytic cell lineage relationships in embryonic rat liver as determined by the differential expression of cytokeratins, alpha-fetoprotein, albumin, and cell surface-exposed components. Cancer Res. 1988; 48: 490918.
  • 28
    Rogler LE. Selective bipotential differentiation of mouse embryonic hepatoblasts in vitro. Am. J. Pathol. 1997; 150: 591602.
  • 29
    Suzuki A, Zheng YW, Kaneko S et al. Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J. Cell Biol. 2002; 156: 17384.
  • 30
    Strick-Marchand H, Morosan S, Charneau P, Kremsdorf D, Weiss MC. Bipotential mouse embryonic liver stem cell lines contribute to liver regeneration and differentiate as bile ducts and hepatocytes. Proc. Natl Acad. Sci. USA 2004; 101: 83605.
  • 31
    Oertel M, Menthena A, Chen YQ, Shafritz DA. Properties of cryopreserved fetal liver stem/progenitor cells that exhibit long-term repopulation of the normal rat liver. Stem Cells 2006; 24: 224451.
  • 32
    Malhi H, Irani AN, Gagandeep S, Gupta S. Isolation of human progenitor liver epithelial cells with extensive replication capacity and differentiation into mature hepatocytes. J. Cell Sci. 2002; 115: 267988.
  • 33
    Nowak G, Ericzon BG, Nava S, Jaksch M, Westgren M, Sumitran-Holgersson S. Identification of expandable human hepatic progenitors which differentiate into mature hepatic cells in vivo. Gut 2005; 54: 9729.
  • 34
    Dan YY, Riehle KJ, Lazaro C et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc. Natl Acad. Sci. USA 2006; 103: 991217.
  • 35
    Heo J, Factor VM, Uren T et al. Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver. Hepatology 2006; 44: 147886.
  • 36
    Choi D, Oh HJ, Chang UJ et al. In vivo differentiation of mouse embryonic stem cells into hepatocytes. Cell Transplant. 2002; 11: 35968.
  • 37
    Teratani T, Yamamoto H, Aoyagi K et al. Direct hepatic fate specification from mouse embryonic stem cells. Hepatology 2005; 41: 83646.
  • 38
    Cai J, Zhao Y, Liu Y et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 2007; 45: 122939.
  • 39
    Chen Y, Soto-Gutierrez A, Navarro-Alvarez N et al. Instant hepatic differentiation of human embryonic stem cells using activin A and a deleted variant of HGF. Cell Transplant. 2006; 15: 86571.
  • 40
    Rambhatla L, Chiu CP, Kundu P, Peng Y, Carpenter MK. Generation of hepatocyte-like cells from human embryonic stem cells. Cell Transplant. 2003; 12: 111.
  • 41
    Ishii T, Yasuchika K, Fujii H et al. In vitro differentiation and maturation of mouse embryonic stem cells into hepatocytes. Exp. Cell Res. 2005; 309: 6877.
  • 42
    Soto-Gutierrez A, Navarro-Alvarez N, Zhao D et al. Differentiation of mouse embryonic stem cells to hepatocyte-like cells by co-culture with human liver nonparenchymal cell lines. Nat. Protoc. 2007; 2: 34756.
  • 43
    Cho CH, Parashurama N, Park EY et al. Homogeneous differentiation of hepatocyte-like cells from embryonic stem cells: applications for the treatment of liver failure. FASEB J. 2008; 22: 898909.
  • 44
    Yamamoto H, Quinn G, Asari A et al. Differentiation of embryonic stem cells into hepatocytes: biological functions and therapeutic application. Hepatology 2003; 37: 98393.
  • 45
    Duan Y, Catana A, Meng Y et al. Differentiation and enrichment of hepatocyte-like cells from human embryonic stem cells in vitro and in vivo. Stem Cells 2007; 25: 305868.
  • 46
    Kumashiro Y, Asahina K, Ozeki R et al. Enrichment of hepatocytes differentiated from mouse embryonic stem cells as a transplantable source. Transplantation 2005; 79: 5507.
  • 47
    Soto-Gutierrez A, Kobayashi N, Rivas-Carrillo JD et al. Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes. Nat. Biotechnol. 2006; 24: 141219.
  • 48
    Alison MR, Poulsom R, Jeffery R et al. Hepatocytes from non-hepatic adult stem cells. Nature 2000; 406: 257.
  • 49
    Theise ND, Badve S, Saxena R et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 2000; 31: 23540.
  • 50
    Lagasse E, Connors H, Al-Dhalimy M et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat. Med. 2000; 6: 122934.
  • 51
    Willenbring H, Bailey AS, Foster M et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat. Med. 2004; 10: 7448.
  • 52
    Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 2004; 305: 903.
  • 53
    Kallis YN, Alison MR, Forbes SJ. Bone marrow stem cells and liver disease. Gut 2007; 56: 71624.
  • 54
    Cantz T, Sharma AD, Jochheim-Richter A et al. Reevaluation of bone marrow-derived cells as a source for hepatocyte regeneration. Cell Transplant. 2004; 13: 65966.
  • 55
    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: 104961.
  • 56
    Vig P, Russo FP, Edwards RJ et al. The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice. Hepatology 2006; 43: 31624.
  • 57
    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: 107787.
  • 58
    Thorgeirsson SS, Grisham JW. Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology 2006; 43: 28.
  • 59
    Sakaida I, Terai S, Yamamoto N et al. Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology 2004; 40: 130411.
  • 60
    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: 7428.
  • 61
    Fang B, Shi M, Liao L, Yang S, Liu Y, Zhao RC. Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation 2004; 78: 838.
  • 62
    Russo FP, Alison MR, Bigger BW et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006; 130: 180721.
  • 63
    Sensken S, Waclawczyk S, Knaupp AS et al. In vitro differentiation of human cord blood-derived unrestricted somatic stem cells towards an endodermal pathway. Cytotherapy 2007; 9: 36278.
  • 64
    Wang Y, Nan X, Li Y et al. Induction of umbilical cord blood-derived beta2m-c-Met+ cells into hepatocyte-like cells by coculture with CFSC/HGF cells. Liver Transpl. 2005; 11: 63543.
  • 65
    Danet GH, Luongo JL, Butler G et al. C1qRp defines a new human stem cell population with hematopoietic and hepatic potential. Proc. Natl Acad. Sci. USA 2002; 99: 104415.
  • 66
    Nonome K, Li XK, Takahara T et al. Human umbilical cord blood-derived cells differentiate into hepatocyte-like cells in the Fas-mediated liver injury model. Am. J. Physiol. Gastrointest. Liver Physiol. 2005; 289: G10919.
  • 67
    Hong SH, Gang EJ, Jeong JA et al. In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells. Biochem. Biophys. Res. Commun. 2005; 330: 115361.
  • 68
    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: 166975.
  • 69
    Zeng F, Chen MJ, Baldwin DA et al. Multiorgan engraftment and differentiation of human cord blood CD34+ Lin- cells in goats assessed by gene expression profiling. Proc. Natl Acad. Sci. USA 2006; 103: 78016.
  • 70
    Di Campli C, Piscaglia AC, Pierelli L et al. A human umbilical cord stem cell rescue therapy in a murine model of toxic liver injury. Dig. Liver Dis. 2004; 36: 60313.
  • 71
    Almeida-Porada G, Porada CD, Chamberlain J, Torabi A, Zanjani ED. Formation of human hepatocytes by human hematopoietic stem cells in sheep. Blood 2004; 104: 258290.
  • 72
    Fujino H, Hiramatsu H, Tsuchiya A et al. Human cord blood CD34+ cells develop into hepatocytes in the livers of NOD/SCID/gamma (c) null mice through cell fusion. FASEB J. 2007; 21: 3499510.
  • 73
    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: 1891900.
  • 74
    Tanabe Y, Tajima F, Nakamura Y et al. Analyses to clarify rich fractions in hepatic progenitor cells from human umbilical cord blood and cell fusion. Biochem. Biophys. Res. Commun. 2004; 324: 71118.
  • 75
    Lee KD, Kuo TK, Whang-Peng J et al. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 2004; 40: 127584.
  • 76
    Aurich I, Mueller LP, Aurich H et al. Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers. Gut 2007; 56: 40515.
  • 77
    Banas A, Teratani T, Yamamoto Y et al. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology 2007; 46: 21928.
  • 78
    Habibullah CM, Syed IH, Qamar A, Taher-Uz Z. Human fetal hepatocyte transplantation in patients with fulminant hepatic failure. Transplantation 1994; 58: 9512.
  • 79
    Strom SC, Fisher RA, Thompson MT et al. Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation 1997; 63: 55969.
  • 80
    Fox IJ, Chowdhury JR, Kaufman SS et al. Treatment of the Crigler–Najjar syndrome type I with hepatocyte transplantation. N. Engl. J. Med. 1998; 338: 14226.
  • 81
    Dhawan A, Mitry RR, Hughes RD. Hepatocyte transplantation for liver-based metabolic disorders. J. Inherited Metabolic Dis. 2006; 29: 4315.
  • 82
    Am Esch JS 2nd, 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: 46370.
  • 83
    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: 22928.
  • 84
    Gordon MY, Levicar N, Pai M et al. Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor. Stem Cells 2006; 24: 182230.
  • 85
    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: 106773.
  • 86
    Gasbarrini A, Rapaccini GL, Rutella S et al. Rescue therapy by portal infusion of autologous stem cells in a case of drug-induced hepatitis. Dig. Liver Dis. 2007; 39: 87882.
  • 87
    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; 13: 335963.
  • 88
    Dezso K, Jelnes P, Laszlo V et al. Thy-1 is expressed in hepatic myofibroblasts and not oval cells in stem cell-mediated liver regeneration. Am. J. Pathol. 2007; 171: 152937.
  • 89
    Meehan RR, Barlow DP, Hill RE, Hogan BL, Hastie ND. Pattern of serum protein gene expression in mouse visceral yolk sac and foetal liver. EMBO J. 1984; 3: 18815.
  • 90
    Brulport M, Schormann W, Bauer A et al. Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers. Hepatology 2007; 46: 86170.
  • 91
    Stevens AM, McDonnell WM, Mullarkey ME, Pang JM, Leisenring W, Nelson JL. Liver biopsies from human females contain male hepatocytes in the absence of transplantation. Lab. Invest. J. Techn Methods Pathol. 2004; 84: 16039.
  • 92
    Takahashi K, Tanabe K, Ohnuki M et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 86172.