Hepatic Progenitors in Development and Transplantation

  • David A. Shafritz
  • Michael Oertel
  • Mariana D. Dabeva
Part of the Molecular Pathology Library book series (MPLB, volume 5)


The rationale for studies to repopulate the liver with transplanted cells is essentially based on three observations: (1) The well-known finding that the liver can fully regenerate after acute hepatotoxic injury or surgical reduction in liver mass, (2) the regenerated liver functions normally, without long-term impairment, and (3) a unique portal (venous to venous) circulation exists in the liver that provides ready access of transplanted cells to the parenchyma through the hepatic sinusoids.


Oval Cell Partial Hepatectomy Fetal Liver Fetal Liver Cell Hepatic Progenitor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to thank Anna Caponigro and Emily Bobe for assistance in typing this manuscript.


  1. 1.
    Higgins GM, Anderson RM. Experimental pathology of the liver. I. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol. 1931;12:186–202.Google Scholar
  2. 2.
    Grisham JW. A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver: autoradiography with thymidine-H3. Cancer Res. 1962;22:842–9.PubMedGoogle Scholar
  3. 3.
    Grisham JW, Thorgeirsson SS. Liver stem cells. In: Potten CS, editor. Stem cells. London: Academic; 1997. p. 233–82.Google Scholar
  4. 4.
    Dong J, Feldman G, Huang J, Wu S, Zhang N, Comerford SA, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–33.PubMedGoogle Scholar
  5. 5.
    Grossman M, Rader DJ, Muller WM, et al. A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolemia. Nat Med. 1995;1:1148–54.PubMedGoogle Scholar
  6. 6.
    Bucher NLR, Swaffield MN. The rate of incorporation of labeled thymidine into the deoxyribonucleic acid of regenerating rat liver in relation to the amount of liver excised. Cancer Res. 1964;240:1611–25.Google Scholar
  7. 7.
    Rajvanshi PA, Kerr A, Bhargava KK, Burk RD, Gupta S. Studies on liver repopulation using the dipeptidyl peptidase IV deficient rat and other rodent recipients: cell size and structure relationships regulate capacity for increased transplanted hepatocytes mass in the liver lobule. Hepatology. 1996;23:482–96.PubMedGoogle Scholar
  8. 8.
    Rajvanshi P, Kerr A, Bhargava KK, Burk RD, Gupta S. Efficacy and safety of repeated hepatocyte transplantation for significant liver repopulation in rodents. Gastroenterology. 1996;111:1092–102.PubMedGoogle Scholar
  9. 9.
    Sangren EP, Palmiter RD, Keckel JL, et al. Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene. Cell. 1991;66:245–56.Google Scholar
  10. 10.
    Rhim J, Sangren EP, Degan JL, Palmiter RD, Brinster RL. Replacement of diseased mouse liver by hepatic cell transplantation. Science. 1994;263:1149–52.PubMedGoogle Scholar
  11. 11.
    Overturf K, Al-Dhalimy M, Tanguay R, Brantly M, Ou CN, Finegold M, et al. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat Genet. 1996;12:266–73.PubMedGoogle Scholar
  12. 12.
    Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet. 1992;340:813–7.PubMedGoogle Scholar
  13. 13.
    Al-Dhalimy M, Overturf K, Finegold M, Grompe M. Long-term therapy with NTBC and tyrosine-restricted diet in a murine model of hereditary tyrosinemia type I. Mol Genet Metab. 2002;75:38–45.PubMedGoogle Scholar
  14. 14.
    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;51:1273–80.Google Scholar
  15. 15.
    Laconi E, Oren R, Mukhopadhyay DK, Hurston E, Laconi S, Pani P, 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.PubMedGoogle Scholar
  16. 16.
    Guo D, Fu T, Nelson JA, Superina RA, Soriano HE. Liver repopulation after cell transplantation in mice treated with retrorsine and carbon tetrachloride. Transplantation. 2002;73:1818–24.PubMedGoogle Scholar
  17. 17.
    Nierhoff D, Ogawa A, Oertel M, Chen YQ, Shafritz DA. Purification and characterization of mouse fetal liver epithelial cells with high in vivo repopulation capacity. Hepatology. 2005;42:130–9.PubMedGoogle Scholar
  18. 18.
    Witek RP, Fisher SH, Petersen BE. Monocrotaline, an alternative to retrorsine-based hepatocyte transplantation in rodents. Cell Transplant. 2005;14:41–7.PubMedGoogle Scholar
  19. 19.
    Oren R, Dabeva M, Petkov P, Hurston E, Laconi E, Shafritz DA. Restoration of normal serum albumin levels in Nagase analbuminemic rats using a newly described strategy for hepatocyte transplantation. Hepatology. 1999;29:75–81.PubMedGoogle Scholar
  20. 20.
    Guha C, Sharma A, Gupta S, Alfieri A, Gorla GR, Gagandeep S, et al. Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatocyte transplantation. Cancer Res. 1999;59:5871–4.PubMedGoogle Scholar
  21. 21.
    Malhi H, Gorla GR, Irani AN, Annamaneni P, Gupta S. Cell transplantation after oxidative hepatic preconditioning with radiation and ischemia-reperfusion leads to extensive liver repopulation. Proc Natl Acad Sci USA. 2002;99:13114–9.PubMedGoogle Scholar
  22. 22.
    Oren R, Dabeva MD, Karnezis AN, Petkov PM, Rosencrantz R, Sandhu JP, et al. Role of thyroid hormone in stimulating liver repopulation by transplanted hepatocytes. Hepatology. 1999;30:903–13.PubMedGoogle Scholar
  23. 23.
    Landis CS, Yamanouchi K, Shou H, Mohan S, Roy-Chowdhury N, Shafritz DA, et al. Noninvasive evaluation of liver repopulation by transplanted hepatocytes using 31P MRS imaging in mice. Hepatology. 2006;44:1250–8.PubMedGoogle Scholar
  24. 24.
    Mignon A, Guidotti JE, Mitchell C, Fabre M, Wernet A, De La Coste A, et al. Selective repopulation of normal mouse liver by Fas/CD-95 resistant hepatocytes. Nat Med. 1998;4:1185–8.PubMedGoogle Scholar
  25. 25.
    Yuan RH, Ogawa A, Ogawa E, Neufeld D, Zhu L, Shafritz DA. p27Kip1 inactivation provides a proliferative advantage to transplanted hepatocytes in DPPIV/Rag2 double knockout mice after repeated host liver injury. Cell Transplant. 2003;12:907–19.PubMedGoogle Scholar
  26. 26.
    Farber E. Similarities of the sequence of the early histological changes induced in the liver of the rat by ethionine, 2-acetylaminofluorene, and 3′-methyl-4-dimethylaminoazobenzene. Cancer Res. 1956;16:142–8.PubMedGoogle Scholar
  27. 27.
    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;139:535–52.PubMedGoogle Scholar
  28. 28.
    Dabeva MD, Shafritz DA. Activation, proliferation and differentiation of progenitor cells into hepatocytes in the D-galactosamine model of liver regeneration. Am J Pathol. 1993;143:1606–20.PubMedGoogle Scholar
  29. 29.
    Sells MA, Katyal SL, Shinozuka H, Estes LW, Sell S, Lombardi B. Isolation of oval cells and transitional cells from the livers of rats fed the carcinogen DL-ethionine. J Natl Cancer Inst. 1981;66:355–62.PubMedGoogle Scholar
  30. 30.
    Akhurst B, Croager EJ, Farley-Roche CA, Ong JK, Dumble ML, Knight B, et al. A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver. Hepatology. 2001;34:519–22.PubMedGoogle Scholar
  31. 31.
    Yin L, Lynch D, Sell S. Participation of different cell types in the restitutive response of the rat liver to periportal injury induced by allyl alcohol. J Hepatol. 1999;31:497–507.PubMedGoogle Scholar
  32. 32.
    Factor VM, Radaeva SA, Thorgeirsson SS. Origin and fate of oval cells in dipin-induced hepatocarcinogenesis in the mouse. Am J Pathol. 1994;145:409–22.PubMedGoogle Scholar
  33. 33.
    Preisegger KH, Factor VM, Fuchsbichler A, Stumptner C, Denk H, Thorgeirsson SS. Atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine mouse model for chronic alcoholic liver disease. Lab Invest. 1999;79:103–9.PubMedGoogle Scholar
  34. 34.
    Tatematsu M, Ho RH, Kaku T, Ekem JK, Farber E. Studies on the proliferation and fate of oval cells in the liver of rats treated with 2-acetylaminofluorine and partial hepatectomy. Am J Pathol. 1984;114:418–30.PubMedGoogle Scholar
  35. 35.
    Evarts RP, Nagy P, Marsden E, Thorgeirsson SS. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis. 1987;8:1737–40.PubMedGoogle Scholar
  36. 36.
    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.PubMedGoogle Scholar
  37. 37.
    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.PubMedGoogle Scholar
  38. 38.
    Omori N, Omori M, Evarts RP, Teramoto T, Miller MJ, Hoang TN, et al. Partial cloning of rat CD34 cDNA and expression during stem cell-dependent liver cell regeneration in the adult rat. Hepatology. 1997;26:720–7.PubMedGoogle Scholar
  39. 39.
    Omori M, Omori N, Evarts RP, Teramoto T, Thorgeirsson SS. Co-expression of flt-3 ligand/flt-3 and SCF/c-kit signal transduction systems in bile duct ligand SI and W mice. Am J Pathol. 1997;150:1179–87.PubMedGoogle Scholar
  40. 40.
    Omori N, Evarts RP, Omori M, Hu Z, Marsden ER, Thorgeirsson SS. Expression of leukemia inhibitory factor and its receptor during liver regeneration in the adult rat. Lab Invest. 1996;75:15–24.PubMedGoogle Scholar
  41. 41.
    Petersen B, 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.PubMedGoogle Scholar
  42. 42.
    Wright N, Samuelson L, Walkup MH, Chandrasekaran P, Gerber DA. Enrichment of a bipotent hepatic progenitor cell from naïve adult liver tissue. Biochem Biophys Res Comm. 2008;366:367–72.PubMedGoogle Scholar
  43. 43.
    Sackett SD, Li Z, Reginald H, Yan G, Wells RG, Brondell K, et al. Fox11 is a marker of bipotential hepatic progenitor cells in mice. Hepatology. 2009;49:920–9.PubMedGoogle Scholar
  44. 44.
    Paku S, Schnur J, Nagy P, Thorgeirsson SS. Origin and structural evolution of the early proliferating oval cells in rat liver. Am J Pathol. 2001;158:1313–23.PubMedGoogle Scholar
  45. 45.
    Crosby HA, Kelly DA, Strain AJ. Human hepatic stem-like cells isolated using c-kit or CD34 can differentiate into biliary epithelium. Gastroenterology. 2001;120:534–44.PubMedGoogle Scholar
  46. 46.
    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.PubMedGoogle Scholar
  47. 47.
    Suzuki A, Zheng Y, Kondo R, Kusakabe M, Takada Y, Fukao K, et al. Flow cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver. Hepatology. 2000;32:1230–9.PubMedGoogle Scholar
  48. 48.
    Tanimizu N, Nishikawa M, Saito H, Tsujimura T, Miyajima A. Isolation of hepatoblasts based on the expression of Dlk/Pref-1. J Cell Sci. 2003;116:1775–86.PubMedGoogle Scholar
  49. 49.
    Dezso K, Jelnes P, László V, Baghy K, Bödör C, Paku S, et al. Thy-1 is expressed in hepatic myofibroblasts and not oval cells in stem cell-mediated liver regeneration. Am J Pathol. 2007;171:1529–37.PubMedGoogle Scholar
  50. 50.
    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. 2007;45:139–49.PubMedGoogle Scholar
  51. 51.
    Yovchev MI, Zhang J, Neufeld DS, Grozdanov PN, Dabeva MD. Thymus cell antigen-1 expressing cells in the oval cell compartment. Hepatology. 2009;50:601–11.PubMedGoogle Scholar
  52. 52.
    Dunsford HA, Sell S. Production of monoclonal antibodies to preneoplastic liver cell populations induced by chemical carcinogens in rats and to transplantable Morris hepatomas. Cancer Res. 1989;49:4887–93.PubMedGoogle Scholar
  53. 53.
    Hixson DC, Faris RA, Thompson NL. An antigenic portrait of the liver during carcinogenesis. Pathobiology. 1990;58:65–77.PubMedGoogle Scholar
  54. 54.
    Faktor VM, Engel’gardt NV, Iazova AK, Lazareva MN, Poltoranina VS, Rudinskaia TD. Common antigens of oval cells and cholangiocytes in the mouse. Their detection by using monoclonal antibodies. Ontogenez. 1990;21:625–32.PubMedGoogle Scholar
  55. 55.
    Dorrell C, Erker L, Lanxon-Cookson KM, Abraham SL, Victoroff T, Ro S, et al. Surface markers for the murine oval cell response. Hepatology. 2008;48:1282–91.PubMedGoogle Scholar
  56. 56.
    Faris RA, Hixson DC. Selective proliferation of chemically altered rat liver epithelial cells following hepatic transplantation. Transplantation. 1989;48:87–92.PubMedGoogle Scholar
  57. 57.
    Dabeva MD, Hwang S-G, Vasa SRG, Hurston E, Novikoff PM, Hixson DC, et al. Differentiation of pancreatic epithelial progenitor cells into hepatocytes following transplantation into rat liver. Proc Natl Acad Sci USA. 1997;94:7356–61.PubMedGoogle Scholar
  58. 58.
    Yechoor V, Liu V, Espiritu C, Paul A, Oka K, Kojima H, et al. Neurogenin3 is sufficient for transdetermination of hepatic progenitor cells into neo-islets in vivo but not transdifferentiation of hepatocytes. Dev Cell. 2009;16:358–73.PubMedGoogle Scholar
  59. 59.
    Wang X, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. Liver repopulation and correction of metabolic liver disease by transplanted adult mouse pancreatic cells. Am J Pathol. 2001;158:571–9.PubMedGoogle Scholar
  60. 60.
    Wang X, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA. 2003;100:11881–8.PubMedGoogle Scholar
  61. 61.
    Song S, Witek RP, Lu Y, Choi YK, Zheng D, Jorgensen M, et al. Ex vivo transduced liver progenitor cells as a platform for gene therapy in mice. Hepatology. 2004;40:918–24.PubMedGoogle Scholar
  62. 62.
    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;47:636–47.PubMedGoogle Scholar
  63. 63.
    Suzuki A, Sekiya S, Onishi M, Oshima N, Kiyonari H, Nakauchi H, et al. Flow cytometric isolation and clonal identification of self-renewing bipotent hepatic progenitor cells in adult mouse liver. Hepatology. 2008;48:1964–78.PubMedGoogle Scholar
  64. 64.
    Arends B, Vankelecom H, Vander Borght S, Roskams T, Penning LC, Rothuizen J, et al. The dog liver contains a “side population” of cells with hepatic progenitor-like characteristics. Stem Cells Dev. 2009;18:343–50.PubMedGoogle Scholar
  65. 65.
    Kubota H, Reid LM. Clonogenic hepatoblasts, common precursors for hepatocytic and biliary lineages, are lacking classical major histocompatibility complex class I antigen. Proc Natl Acad Sci USA. 2000;97:12132–7.PubMedGoogle Scholar
  66. 66.
    Coleman WB, McCullough KD, Esoh GL, Faris RA, Hixson DC, Smith GJ, et al. Evaluation of the differentiation potential of WB-F344 rat liver epithelial stem-like cells in vivo. Differentiation to hepatocytes after transplantation into dipeptidylpeptidase-IV-deficient rat liver. Am J Pathol. 1997;151:353–9.PubMedGoogle Scholar
  67. 67.
    Yasui O, Miura N, Terada K, Kawarada Y, Koyama K, Sugiyama T. Isolation of oval cells from Long-Evans Cinnamon rats and their transformation into hepatocytes in vivo in the rat liver. Hepatology. 1997;25:329–34.PubMedGoogle Scholar
  68. 68.
    Suzuki A, Zheng YW, Kaneko S, Onodera M, Fukao K, Nakauchi H, et al. Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J Cell Biol. 2002;156:173–84.PubMedGoogle Scholar
  69. 69.
    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;101:8360–5.PubMedGoogle Scholar
  70. 70.
    Fougere-Deschatrette C, Imaizumi-Scherrer T, Strick-Marchand H, Morosan S, Charneau P, Kremsdorf D, 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;24:2098–109.PubMedGoogle Scholar
  71. 71.
    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;115:2679–88.PubMedGoogle Scholar
  72. 72.
    Mahieu-Caputo D, Allain JE, Branger J, Coulomb A, Delgado JP, Andreoletti M, et al. Repopulation of athymic mouse liver by cryopreserved early human fetal hepatoblasts. Hum Gene Ther. 2004;15:1219–28.PubMedGoogle Scholar
  73. 73.
    Dan YY, Riehle KJ, Lazaro C, Teoh N, Haque J, Campbell JS, 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;103:9912–7.PubMedGoogle Scholar
  74. 74.
    Sherley JL. Asymmetric cell kinetics genes: the key to expansion of adult stem cells in culture. Stem Cells. 2002;20:561–72.PubMedGoogle Scholar
  75. 75.
    Lechler T, Fuchs E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature. 2005;437:275–80.PubMedGoogle Scholar
  76. 76.
    Lee HS, Crane GG, Merok JR, Tunstead JR, Hatch NL, Panchalingam K, et al. Clonal expansion of adult rat hepatic stem cell lines by suppression of asymmetric cell kinetics (SACK). Biotechnol Bioeng. 2003;83:760–71.PubMedGoogle Scholar
  77. 77.
    Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, et al. Defining the epithelial stem cell niche in skin. Science. 2004;303:359–63.PubMedGoogle Scholar
  78. 78.
    Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell. 2001;104:233–45.PubMedGoogle Scholar
  79. 79.
    Blanpain C, Lowry WE, Geoghehan A, Polak L, Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell. 2004;118:635–48.PubMedGoogle Scholar
  80. 80.
    Kiel MJ, He S, Ashkenazi R, Gentry SN, Teta M, Kushner JA, et al. Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature. 2007;449:238–42.PubMedGoogle Scholar
  81. 81.
    Kuwahara R, Kofman AV, Landis CS, Swenson ES, Barendswaard E, Theise ND. The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology. 2008;47:1994–2002.PubMedGoogle Scholar
  82. 82.
    Marshman E, Booth C, Potten CS. The intestinal epithelial stem cell. Bioessays. 2002;4:91–8.Google Scholar
  83. 83.
    DuBois AM. The embryonic liver. In: Rouiller CH, editor. The liver. New York: Academic; 1963.Google Scholar
  84. 84.
    Zhao R, Duncan SA. Embryonic development of the liver. Hepatology. 2005;41:956–67.PubMedGoogle Scholar
  85. 85.
    Zaret KS, Grompe M. Generation and regeneration of cells of the liver and pancreas. Science. 2008;322:1490–4.PubMedGoogle Scholar
  86. 86.
    Jung J, Zheng M, Goldfarb M, Zaret KS. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science. 1999;284:1998–2003.PubMedGoogle Scholar
  87. 87.
    Rossi JM, Dunn NR, Hogan BLM, Zaret KS. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev. 2001;15:1998–2009.PubMedGoogle Scholar
  88. 88.
    Shiojiri N, Lemire JM, Fausto N. Cell lineages and oval cell progenitors in rat liver development. Cancer Res. 1991;51:2611–20.PubMedGoogle Scholar
  89. 89.
    Fausto N. Liver regeneration. J Hepatol. 2000;32:19–31.PubMedGoogle Scholar
  90. 90.
    Barth RK, Gross KW, Gremke LC, Hastie ND. Developmentally regulated mRNAs in mouse liver. Proc Natl Acad Sci USA. 1982;79:500–4.PubMedGoogle Scholar
  91. 91.
    Meehan RR, Barlow DP, Hill RE, Hogan BL, Hastie ND. Pattern of serum protein gene expression in mouse visceral yolk sac and fetal liver. EMBO J. 1984;3:1881–5.PubMedGoogle Scholar
  92. 92.
    Van Den Hoff MJB, Vermeulen JLM, De Boer PAJ, Lamers WH, Moorman AFM. Developmental changes in the expression of the liver-enriched transcription factors LF-B1, C/EBP, DBP and LAP/LIP in relation to the expression of albumin, α-fetoprotein, carbamoylphosphate synthase and lactase mRNA. Histochem J. 1994;26:20–31.PubMedGoogle Scholar
  93. 93.
    Marceau N, Blouin M-J, Noel M, Torok N, Loranger A. The role of bipotential progenitor cells in liver ontogenesis and neoplasia. In: Sirica AE, editor. The role of cell types in hepatocarcinogenesis. Boca Raton: CRC; 1992. p. 121–49.Google Scholar
  94. 94.
    Tanimizi N, Miyajima A. Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci. 2004;117:3165–74.Google Scholar
  95. 95.
    Dabeva MD, Petkov PM, Sandhu J, Oren R, Laconi E, Hurston E, et al. Proliferation and differentiation of fetal liver epithelial progenitor cells after transplantation into adult rat liver. Am J Pathol. 2000;156:2017–31.PubMedGoogle Scholar
  96. 96.
    Sandhu JS, Petkov PM, Dabeva MD, Shafritz DA. Stem cell properties and repopulation of the rat liver by fetal liver epithelial progenitor cells. Am J Pathol. 2001;159:1323–34.PubMedGoogle Scholar
  97. 97.
    Petkov PM, Zavadil J, Goetz D, Chu T, Carver R, Rogler CE, et al. Gene expression pattern in hepatic stem/progenitor cells during rat fetal development using complementary DNA microarrays. Hepatology. 2004;39:617–27.PubMedGoogle Scholar
  98. 98.
    Van Eyken R, Sciot R, Desmet V. Intrahepatic bile duct development in the rat: a cytokeratin-immunohistochemical study. Lab Invest. 1988;59:52–9.PubMedGoogle Scholar
  99. 99.
    Oertel M, Menthena A, Dabeva MD, Shafritz DA. Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. Gastroenterology. 2006;130:507–20.PubMedGoogle Scholar
  100. 100.
    Haridass D, Yuan Q, Becker PD, Cantz T, Iken M, Rothe M, et al. Repopulation efficiencies of adult hepatocytes, fetal liver progenitor cells, and embryonic stem cell-derived hepatic cells in albumin-promoter-enhancer urokinase-type plasminogen activator mice. Am J Pathol. 2009;175:1483–92.PubMedGoogle Scholar
  101. 101.
    Shafritz DA, Oertel M, Menthena A, Nierhoff D, Dabeva MD. Liver stem cells and prospects for liver reconstitution by transplanted cells. Hepatology. 2006;43:S89–98.PubMedGoogle Scholar
  102. 102.
    Moreno E, Basler K. dMyc transforms cells into super-competitors. Cell. 2004;117:117–29.PubMedGoogle Scholar
  103. 103.
    de la Cova C, Abril M, Bellosta P, Gallant P, Johnston LA. Drosophila myc regulates organ size by inducing cell competition. Cell. 2004;117:107–16.PubMedGoogle Scholar
  104. 104.
    Oertel M, Menthena A, Chen Y-Q, Shafritz DA. Properties of cryopreserved fetal liver stem/progenitor cells that exhibit long-term repopulation of the normal rat liver. Stem Cells. 2006;24:2244–51.PubMedGoogle Scholar
  105. 105.
    Oertel M, Menthena A, Chen Y-Q, Teisner B, Harken-Jensen C, Shafritz DA. Purification of fetal liver stem/progenitor cells containing all the repopulation potential for normal adult rat liver. Gastroenterology. 2008;134:823–32.PubMedGoogle Scholar
  106. 106.
    Goodell MA. Stem-cell “plasticity”: befuddled by the muddle. Curr Opin Hematol. 2003;10:208–13.PubMedGoogle Scholar
  107. 107.
    Wagers AJ, Weissman IL. Plasticity of adult stem cells. Cell. 2004;116:639–48.PubMedGoogle Scholar
  108. 108.
    Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology. 2004;39:1477–87.PubMedGoogle Scholar
  109. 109.
    Thorgeirsson SS, Grisham JW. Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology. 2006;43:2–8.PubMedGoogle Scholar
  110. 110.
    Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, et al. Bone marrow as a potential source of hepatic oval cells. Science. 1999;284:1168–70.PubMedGoogle Scholar
  111. 111.
    Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, et al. Deriviation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology. 2000;31:235–40.PubMedGoogle Scholar
  112. 112.
    Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, et al. Liver from bone marrow in humans. Hepatology. 2000;32:11–6.PubMedGoogle Scholar
  113. 113.
    Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, et al. Hepatocytes from non-hepatic adult stem cells. Nature. 2000;406:257.PubMedGoogle Scholar
  114. 114.
    Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6:1229–34.PubMedGoogle Scholar
  115. 115.
    Menthena A, Deb N, Oertel M, Grozdanov PN, Sandhu J, Shah S, et al. Bone marrow progenitors are not the source of expanding oval cells in injured liver. Stem Cells. 2004;22:1049–61.PubMedGoogle Scholar
  116. 116.
    Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 2002;416:542–5.PubMedGoogle Scholar
  117. 117.
    Ying Q-L, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature. 2002;416:545–8.PubMedGoogle Scholar
  118. 118.
    Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003;422:897–901.PubMedGoogle Scholar
  119. 119.
    Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003;42:901–4.Google Scholar
  120. 120.
    Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 2003;425:968–73.PubMedGoogle Scholar
  121. 121.
    Weimann JM, Johansson CB, Trejo A, Blau HM. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol. 2003;5:959–66.PubMedGoogle Scholar
  122. 122.
    Camargo FD, Finegold M, Goodell MA. Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. J Clin Invest. 2004;113:1266–70.PubMedGoogle Scholar
  123. 123.
    Willenbring H, Bailey AS, Foster M, Akkari Y, Dorrell C, Olson S, et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med. 2004;10:744–8.PubMedGoogle Scholar
  124. 124.
    Camargo FD, Green R, Capetanaki Y, Jackson KA, Goodell MA. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med. 2003;9:1520–7.PubMedGoogle Scholar
  125. 125.
    Newsome PN, Johannessen I, Boyle S, Dalakas E, McAulay KA, Samuel K, 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.PubMedGoogle Scholar
  126. 126.
    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;305:90–3.PubMedGoogle Scholar
  127. 127.
    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;6:532–739.PubMedGoogle Scholar
  128. 128.
    Danet GH, Luongo JL, Butler G, Lu MM, Tenner AJ, Simon MC, et al. ClqRp defines a new human stem cell population with hematopoietic and hepatic potential. Proc Natl Acad Sci USA. 2002;99:10441–5.PubMedGoogle Scholar
  129. 129.
    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 received transplants of highly purified human hematopoietic stem cells. Blood. 2003;101:4201–8.PubMedGoogle Scholar
  130. 130.
    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.PubMedGoogle Scholar
  131. 131.
    Kollet O, Shivtiel S, Chen YQ, Suriawinata J, Thung SN, Dabeva MD, 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.PubMedGoogle Scholar
  132. 132.
    Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest. 2002;109:1291–302.PubMedGoogle Scholar
  133. 133.
    Jiang J, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002;418:41–9.PubMedGoogle Scholar
  134. 134.
    Lee OK, Kuo TK, Chen W-M, Lee K-D, Hsieh S-L, Chen T-H. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood. 2004;103:1669–75.PubMedGoogle Scholar
  135. 135.
    Brulport M, Schormann W, Bauer A, Hermes M, Elsner C, Hammersen FJ, et al. Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers. Hepatology. 2007;46:861–70.PubMedGoogle Scholar
  136. 136.
    Kuo TK, Hung SP, Chuang CH, Chen CT, Shih YR, Fang SC, et al. Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology. 2008;134:2111–21.PubMedGoogle Scholar
  137. 137.
    Anjos-Afonso F, Siapati EK, Bonnet D. In vivo contribution of murine mesenchymal stem cells into multiple cell types under minimal damage conditions. J Cell Sci. 2004;117:5655–64.PubMedGoogle Scholar
  138. 138.
    Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M, et al. Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood. 2005;106:756–63.PubMedGoogle Scholar
  139. 139.
    Aurich I, Mueller LP, Aurich H, Luetzkendorf J, Tisljar K, Dollinger M, et al. Functional integration of human mesenchymal stem cell-derived hepatocytes into mouse livers. Gut. 2007;56:405–15.PubMedGoogle Scholar
  140. 140.
    Banas A, Teratani T, Yamamoto Y, Tokuhara M, Takeshita F, Quinn G, et al. Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Hepatology. 2007;46:219–28.PubMedGoogle Scholar
  141. 141.
    Sgodda M, Aurich H, Kleist S, Aurich I, König S, Dollinger MM, et al. Hepatocyte differentiation of mesencymal stem cells from rat peritoneal adipose tissue in vitro and in vivo. Exp Cell Res. 2007;313:2875–86.PubMedGoogle Scholar
  142. 142.
    Hamazaki T, Iiboshi Y, Oka M, Papst PJ, Meacheam AM, Zon LI, et al. Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett. 2001;497:15–9.PubMedGoogle Scholar
  143. 143.
    Jones EA, Tosh D, Wilson DI, Lindsay S, Forrester LM. Hepatic differentiation of murine embryonic stem cells. Exp Cell Res. 2002;272:15–22.PubMedGoogle Scholar
  144. 144.
    Yamada T, Yoshikawa M, Kanda S, Kato Y, Nakajima Y, Ishizaka S, et al. In vitro differentiation of embryonic stem cells into hepatocyte-like cells identified by cellular uptake of indocyanine green. Stem Cells. 2002;20:146–54.PubMedGoogle Scholar
  145. 145.
    Yamamoto H, Quinn G, Asari A, Yamanokuchi H, Teratani T, Terada M, et al. Differentiation of embryonic stem cells into hepatocytes: Biological functions and therapeutic application. Hepatology. 2003;37:983–93.PubMedGoogle Scholar
  146. 146.
    Rambhatla L, Chiu CP, Kundu P, Peng Y, Carpenter MK. Generation of hepatocyte-like cells from human embryonic stem cells. Cell Transplant. 2003;12:1–11.PubMedGoogle Scholar
  147. 147.
    Kubo A, Shinozaki K, Shannon JM, Kouskoff V, Kennedy M, Woo S, et al. Development of definitive endoderm from embryonic stem cells in culture. Development. 2004;131:1651–62.PubMedGoogle Scholar
  148. 148.
    Gouon-Evans V, Boussemart L, Gadue P, Nierhoff D, Koehler CI, Kubo A, et al. BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol. 2006;24:1402–11.PubMedGoogle Scholar
  149. 149.
    Heo J, Factor JM, Uren T, Takahama Y, Lee JS, Major M, et al. Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver. Hepatology. 2006;44:1478–86.PubMedGoogle Scholar
  150. 150.
    Duan Y, Catana A, Meng Y, Yamamoto N, He S, Gupta S, et al. Differentiation and enrichment of hepatocyte-like cells from human embryonic stem cells in vitro and in vivo. Stem Cells. 2007;25:3058–68.PubMedGoogle Scholar
  151. 151.
    Basma H, Soto-Gutiérrez A, Yannam GR, Liu L, Ito R, Yamamoto T, et al. Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology. 2009;136:990–9.PubMedGoogle Scholar
  152. 152.
    Slack JMW. Origin of stem cells in organogenesis. Organ Dev. 2008;322:1498–501.Google Scholar
  153. 153.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72.PubMedGoogle Scholar
  154. 154.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.PubMedGoogle Scholar
  155. 155.
    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.PubMedGoogle Scholar
  156. 156.
    Hochedlinger K, Plath K. Epigenetic reprogramming and induced pluripotency. Development. 2009;136:509–23.PubMedGoogle Scholar
  157. 157.
    Roskams T, Van Den OJJ, De Vos R, Desmer VJ. Neuroendocrine features of reactive bile ductules in cholestatis liver disease. Am J Pathol. 1990;137:1019–25.PubMedGoogle Scholar
  158. 158.
    Demetris AJ, Seaberg EE, Wennerberg A, Lonellie J, Michalopoulos G. Ductular reaction after submassive necrosis in humans: special emphasis on analysis of ductular hepatocytes. Am J Pathol. 1996;149:439–48.PubMedGoogle Scholar
  159. 159.
    Roskams T, De Vos R, Van Eyken P, Myazaki H, Van Damme B, Desmer 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.PubMedGoogle Scholar
  160. 160.
    Roskams TA, Theise ND, Balabaud C, Bhagat G, Bhathal PS, Bioulac-Sage P, et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology. 2004;39:1739–45.PubMedGoogle Scholar
  161. 161.
    Zhou H, Rogler LE, Teperman L, Morgan G, Rogler CE. Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver. Hepatology. 2007;45:716–24.PubMedGoogle Scholar
  162. 162.
    Haruna Y, Saito K, Spaulding S, Nalesnik MA, Gerber MA. Identification of bipotential progenitor cells in human liver development. Hepatology. 1996;23:476–81.PubMedGoogle Scholar
  163. 163.
    Schmelzer E, Wauthier E, Reid L. The phenotypes of pluripotent human hepatic progenitors. Stem Cells. 2006;24:1852–8.PubMedGoogle Scholar
  164. 164.
    Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao HL, et al. Human hepatic stem cells from fetal and postnatal donors. J Exp Med. 2007;204:1973–87.PubMedGoogle Scholar
  165. 165.
    Dandri M, Burda MR, Török E, Pollok JM, Iwanska A, Sommer G, et al. Repopulation of mouse liver with human hepatocytes and in vivo infection with hepatitis B virus. Hepatology. 2001;33:981–8.PubMedGoogle Scholar
  166. 166.
    Tateno C, Yoshizane Y, Saito N, Kataoka M, Utoh R, Yamasaki C, et al. Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am J Pathol. 2004;165:901–12.PubMedGoogle Scholar
  167. 167.
    Meuleman P, Libbrecht L, De Vos R, de Hemptinne B, Gevaert K, Vandekerckhove J, et al. Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera. Hepatology. 2005;41:847–56.PubMedGoogle Scholar
  168. 168.
    Azuma H, Paulk N, Ranade A, Dorrell C, Al-Dhalimy M, Ellis E, et al. Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/I12rg−/− mice. Nat Biotechnol. 2007;25:903–10.PubMedGoogle Scholar
  169. 169.
    Yoshida Y, Tokusashi Y, Lee GH, Ogawa K. Intrahepatic transplantation of normal hepatocytes prevents Wilson’s disease in Long-Evans cinnamon rats. Gastroenterology. 1996;111:1654–60.PubMedGoogle Scholar
  170. 170.
    Teckman JH, An JK, Blomenkamp K, Schmidt B, Perlmutter D. Mitochondrial autophagy and injury in the liver in alpha 1-antitrypsin deficiency. Am J Physiol Gastrointestinal Liver Physiol. 2004;286:G851–62.Google Scholar
  171. 171.
    Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci USA 2010;107:1437–42.Google Scholar
  172. 172.
    Si-Tayeb K, Noto FK, Nagaoka M, Li J, Battle MA, Duris C, et al. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology. 2010;51:297–305.Google Scholar
  173. 173.
    Sullivan GJ, Hay DC, Park IH, Fletcher J, Hannoun Z, Payne CM, et al. Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology. 2010;51:329–35.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • David A. Shafritz
    • 1
  • Michael Oertel
  • Mariana D. Dabeva
  1. 1.Department of Medicine, Cell Biology and Pathology, Marion Bessin Liver Research CenterAlbert Einstein College of Medicine of Yeshiva UniversityNew YorkUSA

Personalised recommendations