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Fetal liver cell transplantation as a potential alternative to whole liver transplantation?

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Abstract

Because organ shortage is the fundamental limitation of whole liver transplantation, novel therapeutic options, especially the possibility of restoring liver function through cell transplantation, are urgently needed to treat end-stage liver diseases. Groundbreaking in vivo studies have shown that transplanted hepatocytes are capable of repopulating the rodent liver. The two best studied models are the urokinase plasminogen activator (uPA) transgenic mouse and the fumarylacetoacetate hydrolase (FAH)-deficient mouse, in which genetic modifications of the recipient liver provide a tissue environment in which there is extensive liver injury and selection pressure favoring the proliferation and survival of transplanted hepatocytes. Because transplanted hepatocytes do not significantly repopulate the (near-)normal liver, attention has been focused on finding alternative cell types, such as stem or progenitor cells, that have a higher proliferative potential than hepatocytes. Several sources of stem cells or stem-like cells have been identified and their potential to repopulate the recipient liver has been evaluated in certain liver injury models. However, rat fetal liver stem/progenitor cells (FLSPCs) are the only cells identified to date that can effectively repopulate the (near-)normal liver, are morphologically and functionally fully integrated into the recipient liver, and remain viable long-term. Even though primary human fetal liver cells are not likely to be routinely used for clinical liver cell repopulation in the future, using or engineering candidate cells exhibiting the characteristics of FLSPCs suggests a new direction in developing cell transplantation strategies for therapeutic liver replacement. This review will give a brief overview concerning the existing animal models and cell sources that have been used to restore normal liver structure and function, and will focus specifically on the potential of FLSPCs to repopulate the liver.

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References

  1. Ribbert H. Über Veränderungen transplantirter Gewebe. Arch Entwickl Mech Organ. 1898;6:131–47.

    Article  Google Scholar 

  2. Lubarsch O. Ueber Gewebsembolieen und Gewebsverlagerungen. Verhandl d Deutsch Patholog Gesellschaft. 1899;1:97–103.

    Google Scholar 

  3. Mitsuda. Untersuchungen über Transplantation und Explantation von Lebergewebe unter besonderer berücksichtigung der Pigmentfarbe. Virchows Arch. 1924;248:91–100.

  4. Cameron GR, Oakley GS. Transplantation of liver. J Pathol. 1934;38:17–28.

    Article  Google Scholar 

  5. Böck J, Popper H. Über lebertransplantation in die Vorderkammer des Auges. Virchows Arch. 1937;299:219–34.

    Article  Google Scholar 

  6. Grisham JW, Leong GF, Hole BV. Heterotopic partial autotransplantation of rat liver: technic and demonstration of structure and function of the graft. 1964;24:1474–95.

  7. Welch CS. A note on transplantation of the whole liver in dogs. Transplant Bull. 1955;2:54–5.

    Google Scholar 

  8. Starzl TE, Marchiore TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the liver in humans. Surg Gynecol Obstet. 1963;117:659–76.

    PubMed  CAS  Google Scholar 

  9. Starzl TE, Fung JJ. Themes of liver transplantation. Hepatology. 2010;51:1869–84.

    Article  PubMed  Google Scholar 

  10. Merion RM. Current status and future of liver transplantation. Semin Liver Dis. 2010;30:411–21.

    Article  PubMed  Google Scholar 

  11. Matas AJ, Sutherland DER, Steffes MW, Mauer SM, Sowe A, Simmons RL, et al. Hepatocellular transplantation for metabolic deficiencies: decrease of plasma bilirubin in Gunn rats. Science. 1976;192:892–4.

    Article  PubMed  CAS  Google Scholar 

  12. Gunn CK. Hereditary acholuric jaundice. J Hered. 1938;29:137–9.

    Google Scholar 

  13. Schmid R, Hammaker L. Metabolism and disposition of C14-bilirubin in congenital nonhemolytic jaundice. J Clin Invest. 1963;42:1720–34.

    Article  PubMed  CAS  Google Scholar 

  14. Jirtle RL, Biles C, Michalopoulos G. Morphologic and histochemical analysis of hepatocytes transplanted into syngeneic hosts. Am J Pathol. 1980;101:115–26.

    PubMed  CAS  Google Scholar 

  15. Kusano M, Mito M. Observations on the fine structure of long-survived isolated hepatocytes inoculated into rat spleen. Gastroenterology. 1982;82:616–28.

    PubMed  CAS  Google Scholar 

  16. Minato M, Houssin D, Demma I, Morin J, Gigou M, Szekely AM, et al. Transplantation of hepatocytes for treatment of surgically induced acute hepatic failure in the rat. Eur Surg Res. 1984;16:162–9.

    Article  PubMed  CAS  Google Scholar 

  17. Kondo T, Watanabe Y. A heritable hyperlipemic rabbit. Jikken Dobutsu. 1975;24:89–94.

    PubMed  CAS  Google Scholar 

  18. Wiederkehr JC, Kondos GT, Pollak R. Hepatocyte transplantation for the low-density lipoprotein receptor-deficient state. A study in the Watanabe rabbit. Transplantation. 1990;50:466–71.

    Article  PubMed  CAS  Google Scholar 

  19. Kacser H, Bulfield G, Wallace ME. Histidinaemic mutant in the mouse. Nature. 1973;244:77–9.

    Article  PubMed  CAS  Google Scholar 

  20. Selden C, Calnan D, Morgan N, Wilcox H, Carr E, Hodgson HJ. Histidinemia in mice: a metabolic defect treated using a novel approach to hepatocellular transplantation. Hepatology. 1995;21:1405–12.

    PubMed  CAS  Google Scholar 

  21. Trimble HC, Keeler CE. The inheritance of “high uric acid excretion” in dogs. J Hered. 1938;29:288–91.

    Google Scholar 

  22. Kocken JM, Borel Rinkes IH, Bijma AM, de Roos WK, Bouwman E, Terpstra OT, et al. Correction of an inborn error of metabolism by intraportal hepatocyte transplantation in a dog model. Transplantation. 1996;62:358–64.

    Article  PubMed  CAS  Google Scholar 

  23. Sasaki M, Yoshida MC, Kagami K, Takeichi N, Kobayashi H, Dempo K, et al. Spontaneous hepatitis in an inbred strain of Long-Evans rats. Rat News Lett. 1985;14:4–6.

    Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. Higgins GM, Anderson RM. Experimental pathology of the liver: I. Restoration of the liver in the white rat following partial removal. Arch Pathol. 1931;12:186–202.

    Google Scholar 

  26. Bucher NRL, Malt RA. Regeneration of liver and kidney. Little, Brown and Co., Boston, 1971;17–176.

  27. Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006;43:S45–53.

    Article  PubMed  CAS  Google Scholar 

  28. Michalopoulos GK. Liver regeneration. J Cell Physiol. 2007;213:286–300.

    Article  PubMed  CAS  Google Scholar 

  29. Jirtle RL, Michalopoulos G. Effects of partial hepatectomy on transplanted hepatocytes. Cancer Res. 1982;42:3000–4.

    PubMed  CAS  Google Scholar 

  30. Rhim J, Sangren EP, Degen JL, Palmiter RD, Brinster RL. Replacement of diseased mouse liver by hepatic cell transplantation. Science. 1994;263:1149–52.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. Laconi E, Oren R, Mukhopadhay D, Hurston E, Laconi S, Pani P, et al. Long-term, near total liver replacement by transplantation of isolated hepatocytes. Am J Pathol. 1998;153:319–29.

    Article  PubMed  CAS  Google Scholar 

  33. Witek RP, Fisher SH, Petersen BE. Monocrotaline, an alternative to retrorsine-based hepatocyte transplantation in rodents. Cell Transplant. 2005;14:41–7.

    Article  PubMed  Google Scholar 

  34. 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 hepatocytes transplantation. Cancer Res. 1999;59:5871–4.

    PubMed  CAS  Google Scholar 

  35. Sandgren EP, Palmiter RD, Heckel JL, Daugherty CC, Brinster RL, Degen JL. Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene. Cell. 1991;66:245–56.

    Article  PubMed  CAS  Google Scholar 

  36. Grompe M, al-Dhalimy M, Finegold M, Ou CN, Burlingame T, Kennaway NG, et al. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev. 1993;7:2298–307.

    Article  PubMed  CAS  Google Scholar 

  37. Peterson JE. Effects of the pyrrolizidine alkaloid lasiocarpine-N-oxide on nuclear and cell division in the liver of rats. J Pathol Bacteriol. 1965;89:153–71.

    Article  PubMed  CAS  Google Scholar 

  38. Samuel A, Jago MV. Localization in the cell cycle of the antimitotic action of the pyrrolizidine alkaloid, lasiocarpine and of its metabolite, dehydroheliotridine. Chem Biol Interact. 1975;10:185–97.

    Article  PubMed  CAS  Google Scholar 

  39. Chesney CF, Allen JR, Hsu I. Effect of monocrotaline, a pyrrolizidine alkaloid, on regenerating rat liver. Res Commun Chem Pathol Pharmacol. 1973;5:859–62.

    PubMed  CAS  Google Scholar 

  40. Oren R, Dabeva MD, Karnezis AN, Petkov PM, Rosencrantz R, Sandhu JP, et al. Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes. Hepatology. 1999;30:903–13.

    Article  PubMed  CAS  Google Scholar 

  41. 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.

    Article  PubMed  CAS  Google Scholar 

  42. Joseph B, Kumaran V, Berishvili E, Bhargava KK, Palestro CJ, Gupta S. Monocrotaline promotes transplanted cell engraftment and advances liver repopulation in rats via liver conditioning. Hepatology. 2006;44:1411–20.

    Article  PubMed  CAS  Google Scholar 

  43. Mignon A, Guidotti JE, Mitchell C, Fabre M, Wernet A, De La Coste A, et al. Selective repopulation of normal mouse liver by Fas/CD95-resistant hepatocytes. Nat Med. 1998;4:1185–8.

    Article  PubMed  CAS  Google Scholar 

  44. 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.

    PubMed  Google Scholar 

  45. Brezillon N, Lambert-Blot M, Morosan S, Couton D, Mitchell C, Kremsdorf D, et al. Transplanted hepatocytes over-expressing FoxM1B efficiently repopulate chronically injured mouse liver independent of donor age. Mol Ther. 2007;15:1710–5.

    Article  PubMed  CAS  Google Scholar 

  46. Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, et al. Treatment of the Crigler–Najjar syndrome type 1 with hepatocyte transplantation. New Engl J Med. 1998;338:1422–6.

    Article  PubMed  CAS  Google Scholar 

  47. Loeffler M, Potten CS. Stem cells and cellular pedigrees—a conceptual introduction. In: Potten CS, editor. Stem cells. London: Academic Press; 1997. p. 1–29.

    Chapter  Google Scholar 

  48. Oertel M, Shafritz DA. Stem cells, cell transplantation and liver repopulation. Biochim Biophys Acta. 2008;1782:61–74.

    PubMed  CAS  Google Scholar 

  49. Dan YY, Yeoh GC. Liver stem cells: a scientific and clinical perspective. J Gastroenterol Hepatol. 2008;23:687–98.

    Article  PubMed  Google Scholar 

  50. Kung JW, Forbes SJ. Stem cells and liver repair. Curr Opin Biotechnol. 2009;20:568–74.

    Article  PubMed  CAS  Google Scholar 

  51. Zhao Q, Ren H, Zhu D, Han Z. Stem/progenitor cells in liver injury repair and regeneration. Biol Cell. 2009;101:557–71.

    PubMed  Google Scholar 

  52. Schwartz RE, Verfaillie C. Hepatic stem cells. Methods Mol Biol. 2010;640:167–79.

    Article  PubMed  CAS  Google Scholar 

  53. Sangan CB, Tosh D. Hepatic progenitor cells. Cell Tissue Res. 2010;342:131–7.

    Article  PubMed  Google Scholar 

  54. Kisseleva T, Gigante E, Brenner DA. Recent advances in liver stem cell therapy. Curr Opin Gastroenterol. 2010;26:395–402.

    Article  PubMed  Google Scholar 

  55. 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.

    PubMed  CAS  Google Scholar 

  56. 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.

    PubMed  CAS  Google Scholar 

  57. 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.

    PubMed  CAS  Google Scholar 

  58. 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.

    Article  PubMed  CAS  Google Scholar 

  59. 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.

    Article  PubMed  CAS  Google Scholar 

  60. 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.

    Article  PubMed  CAS  Google Scholar 

  61. Lázaro CA, Rhim JA, Yamada Y, Fausto N. Generation of hepatocytes from oval cell precursors in culture. Cancer Res. 1998;58:5514–22.

    PubMed  Google Scholar 

  62. 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.

    Article  PubMed  CAS  Google Scholar 

  63. 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.

    PubMed  CAS  Google Scholar 

  64. 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.

    Article  PubMed  CAS  Google Scholar 

  65. Theise ND, Badve S, Saxena R, Henegariu O, Sell S, Crawford JM, et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology. 2000;31:235–40.

    Article  PubMed  CAS  Google Scholar 

  66. 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.

    Article  PubMed  CAS  Google Scholar 

  67. 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.

    Article  PubMed  CAS  Google Scholar 

  68. 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.

    Article  PubMed  CAS  Google Scholar 

  69. 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.

    Article  PubMed  Google Scholar 

  70. 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  72. 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.

    Article  PubMed  CAS  Google Scholar 

  73. Thorgeirsson SS, Grisham JW. Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology. 2006;43:2–8.

    Article  PubMed  Google Scholar 

  74. Danet GH, Luongo JL, Butler G, Lu MM, Tenner AJ, Simon MC, et al. C1qRp defines a new human stem cell population with hematopoietic and hepatic potential. Proc Natl Acad Sci USA. 2002;99:10441–5.

    Article  PubMed  CAS  Google Scholar 

  75. 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.

    Article  PubMed  CAS  Google Scholar 

  76. 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.

    Article  PubMed  Google Scholar 

  77. 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.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  79. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.

    Article  PubMed  CAS  Google Scholar 

  80. Jiang Y, 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.

    Article  PubMed  CAS  Google Scholar 

  81. Aurich I, Mueller LP, Aurich H, Luetzkendorf J, Tisljar K, Dollinger MM, et al. Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers. Gut. 2007;56:405–15.

    Article  PubMed  CAS  Google Scholar 

  82. 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.

    Article  PubMed  Google Scholar 

  83. 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.

    Article  PubMed  Google Scholar 

  84. Cho KA, Ju SY, Cho SJ, Jung YJ, Woo SY, Seoh JY, et al. Mesenchymal stem cells showed the highest potential for the regeneration of injured liver tissue compared with other subpopulations of the bone marrow. Cell Biol Int. 2009;33:772–7.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  86. Campard D, Lysy PA, Najimi M, Sokal EM. Native umbilical cord matrix stem cells express hepatic markers and differentiate into hepatocyte-like cells. Gastroenterology. 2008;134:833–48.

    Article  PubMed  CAS  Google Scholar 

  87. Sgodda M, Aurich H, Kleist S, Aurich I, König S, Dollinger MM, et al. Hepatocyte differentiation of mesenchymal stem cells from rat peritoneal adipose tissue in vitro and in vivo. Exp Cell Res. 2007;313:2875–86.

    Article  PubMed  CAS  Google Scholar 

  88. 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.

    Article  PubMed  CAS  Google Scholar 

  89. Aurich H, Sgodda M, Kaltwasser P, Vetter M, Weise A, Liehr T, et al. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo. Gut. 2009;58:570–81.

    Article  PubMed  CAS  Google Scholar 

  90. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–6.

    Article  PubMed  CAS  Google Scholar 

  91. De Miguel MP, Arnalich Montiel F, Lopez Iglesias P, Blazquez Martinez A, Nistal M. Epiblast-derived stem cells in embryonic and adult tissues. Int J Dev Biol. 2009;53:1529–40.

    Article  PubMed  Google Scholar 

  92. Nichols J, Smith A. The origin and identity of embryonic stem cells. Development. 2011;138:3–8.

    Article  PubMed  CAS  Google Scholar 

  93. Hamazaki T, Iiboshi Y, Oka M, Papst PJ, Meacham AM, Zon LI, et al. Hepatic maturation in differentiating embryonic stem cells in vitro. FEBS Lett. 2001;497:15–9.

    Article  PubMed  CAS  Google Scholar 

  94. Kumashiro Y, Asahina K, Ozeki R, Shimizu-Saito K, Tanaka Y, Kida Y, et al. Enrichment of hepatocytes differentiated from mouse embryonic stem cells as a transplantable source. Transplantation. 2005;79:550–7.

    Article  PubMed  Google Scholar 

  95. Heo J, Factor VM, 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.

    Article  PubMed  CAS  Google Scholar 

  96. 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.

    Article  PubMed  CAS  Google Scholar 

  97. Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H, et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology. 2007;45:1229–39.

    Article  PubMed  CAS  Google Scholar 

  98. 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.

    Article  PubMed  CAS  Google Scholar 

  99. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  101. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    Article  PubMed  CAS  Google Scholar 

  102. 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.

    Article  PubMed  CAS  Google Scholar 

  103. Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, Chiba T, et al. Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science. 2008;321:699–702.

    Article  PubMed  CAS  Google Scholar 

  104. Li W, Wang D, Qin J, Liu C, Zhang Q, Zhang X, et al. Generation of functional hepatocytes from mouse induced pluripotent stem cells. J Cell Physiol. 2010;222:492–501.

    PubMed  CAS  Google Scholar 

  105. 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.

    PubMed  CAS  Google Scholar 

  106. Gai H, Nguyen DM, Moon YJ, Aguila JR, Fink LM, Ward DC, et al. Generation of murine hepatic lineage cells from induced pluripotent stem cells. Differentiation. 2010;79:171–81.

    Article  PubMed  CAS  Google Scholar 

  107. 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.

    Article  PubMed  CAS  Google Scholar 

  108. Espejel S, Roll GR, McLaughlin KJ, Lee AY, Zhang JY, Laird DJ, et al. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. J Clin Invest. 2010;120:3120–6.

    Article  PubMed  CAS  Google Scholar 

  109. Greenbaum LE. From skin cells to hepatocytes: advances in application of iPS cell technology. J Clin Invest. 2010;120:3102–5.

    Article  PubMed  CAS  Google Scholar 

  110. Lengemann P. Ueber die Schicksale verlagerter und embolisierter Gewebsteile im tierischen Körper. In: Lubarsch O, editor. Zur Lehre von den Geschwülsten und Infektionskrankheiten. Wiesbaden: Verlag von J. F. Bergmann; 1899. p. 1–75.

    Google Scholar 

  111. Nichols EH. Implantation of tissue and its relation to cancer. J Med Res. 1906;13:187–233.

    Google Scholar 

  112. Leduc EH, Wilson JW. Production of transplantable hepatomas by intrasplenic implantation of normal liver in the mouse. J Natl Cancer Inst. 1963;30:85–99.

    PubMed  CAS  Google Scholar 

  113. Ebata H, Mito M. Intrasplenic fetal rat hepatic tissue isotransplantation. Transplantation. 1985;39:77–9.

    Article  PubMed  CAS  Google Scholar 

  114. Ebata H, Onodera K, Sawa M, Mito M. A study of liver regeneration using fetal rat liver tissue transplanted into the spleen. Jpn J Surg. 1988;18:540–7.

    Article  PubMed  CAS  Google Scholar 

  115. Wilson JW, Groat CS, Leduc EH. Histogenesis of the liver. Ann N Y Acad Sci. 1963;111:8–24.

    Article  PubMed  CAS  Google Scholar 

  116. Douarin NM. An experimental analysis of liver development. Med Biol. 1975;53:427–55.

    PubMed  CAS  Google Scholar 

  117. Houssaint E. Differentiation of the mouse hepatic primordium. I. An analysis of tissue interactions in hepatocyte differentiation. Cell Differ. 1980;9:269–79.

    Article  PubMed  CAS  Google Scholar 

  118. Schmid P, Schulz WA. Coexpression of the c-myc protooncogene with alpha-fetoprotein and albumin in fetal mouse liver. Differentiation. 1990;45:96–102.

    Article  PubMed  CAS  Google Scholar 

  119. Cascio S, Zaret KS. Hepatocyte differentiation initiates during endodermal-mesenchymal interactions prior to liver formation. Development. 1991;113:217–25.

    PubMed  CAS  Google Scholar 

  120. Shiojiri N, Lemire JM, Fausto N. Cell lineages and oval cell progenitors in rat liver development. Cancer Res. 1991;51:2611–20.

    PubMed  CAS  Google Scholar 

  121. 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;48:4909–18.

    PubMed  CAS  Google Scholar 

  122. Brill S, Zvibel I, Reid LM. Maturation-dependent changes in the regulation of liver-specific gene expression in embryonal versus adult primary liver cultures. Differentiation. 1995;59:95–102.

    Article  PubMed  CAS  Google Scholar 

  123. Blouin MJ, Lamy I, Loranger A, Noël M, Corlu A, Guguen-Guillouzo C, et al. Specialization switch in differentiating embryonic rat liver progenitor cells in response to sodium butyrate. Exp Cell Res. 1995;217:22–30.

    Article  PubMed  CAS  Google Scholar 

  124. Taniguchi H, Kondo R, Suzuki A, Zheng YW, Takada Y, et al. Clonogenic colony-forming ability of flow cytometrically isolated hepatic progenitor cells in the murine fetal liver. Cell Transplant. 2000;9:697–700.

    PubMed  CAS  Google Scholar 

  125. 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.

    Article  PubMed  CAS  Google Scholar 

  126. 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.

    Article  PubMed  CAS  Google Scholar 

  127. Nitou M, Sugiyama Y, Ishikawa K, Shiojiri N. Purification of fetal mouse hepatoblasts by magnetic beads coated with monoclonal anti-e-cadherin antibodies and their in vitro culture. Exp Cell Res. 2002;279:330–43.

    Article  PubMed  CAS  Google Scholar 

  128. 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.

    Article  PubMed  CAS  Google Scholar 

  129. Cantz T, Zuckerman DM, Burda MR, Dandri M, Göricke B, Thalhammer S, et al. Quantitative gene expression analysis reveals transition of fetal liver progenitor cells to mature hepatocytes after transplantation in uPA/RAG-2 mice. Am J Pathol. 2003;162:37–45.

    Article  PubMed  CAS  Google Scholar 

  130. 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.

    Article  PubMed  Google Scholar 

  131. 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.

    Article  PubMed  CAS  Google Scholar 

  132. Suzuki A, Zheng YW, Fukao K, Nakauchi H, Taniguchi H. Liver repopulation by c-Met-positive stem/progenitor cells isolated from the developing rat liver. Hepatogastroenterology. 2004;51:423–6.

    PubMed  CAS  Google Scholar 

  133. Jensen CH, Jauho EI, Santoni-Rugiu E, Holmskov U, Teisner B, Tygstrup N, et al. Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta-like protein/preadipocyte factor 1/fetal antigen 1. Am J Pathol. 2004;164:1347–59.

    Article  PubMed  CAS  Google Scholar 

  134. Thompson NL, Hixson DC, Callanan H, Panzica M, Flanagan D, Faris RA, et al. A Fischer rat substrain deficient in dipeptidyl peptidase IV activity makes normal steady-state RNA levels and an altered protein. Use as a liver-cell transplantation model. Biochem J. 1991;237:497–502.

    Google Scholar 

  135. Rajvanshi PA, Kerr A, Bhargava KK, Burk RD, Gupta S. Studies of 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.

    Article  PubMed  CAS  Google Scholar 

  136. 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.

    Article  PubMed  CAS  Google Scholar 

  137. Sigal SH, Brill S, Reid LM, Zvibel I, Gupta S, Hixson D, et al. Characterization and enrichment of fetal rat hepatoblasts by immunoadsorption (“panning”) and fluorescence-activated cell sorting. Hepatology. 1994;19:999–1006.

    PubMed  CAS  Google Scholar 

  138. 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.

    Article  PubMed  CAS  Google Scholar 

  139. Oertel M, Menthena A, Dabeva MD, Shafritz DA. Cell competition leads to high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. Gastroenterology. 2006;130:507–20.

    Article  PubMed  Google Scholar 

  140. 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.

    Article  PubMed  CAS  Google Scholar 

  141. Fiegel HC, Park JJ, Lioznov MV, Martin A, Jaeschke-Melli S, Kaufmann PM, et al. Characterization of cell types during rat liver development. Hepatology. 2003;37:148–54.

    Article  PubMed  Google Scholar 

  142. Isabel Z, Miri B, Einav H, Ella BL, Zamir H, Ran O. Isolation, characterization and culture of Thy1-positive cells from fetal rat livers. World J Gastroenterol. 2006;12:3841–7.

    PubMed  CAS  Google Scholar 

  143. Oertel M, Menthena A, Chen Y-Q, Shafritz DA. Comparison of hepatic properties and transplantation of Thy1+ and Thy-1− cells isolated from ED14 rat fetal liver. Hepatology. 2007;46:1236–45.

    Article  PubMed  CAS  Google Scholar 

  144. 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.

    Article  PubMed  CAS  Google Scholar 

  145. 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.

    Article  PubMed  CAS  Google Scholar 

  146. Morata G, Ripoll P. Minutes: mutants of Drosophila autonomously affecting cell division rate. Dev Biol. 1975;42:211–21.

    Article  PubMed  CAS  Google Scholar 

  147. Moreno E, Basler K. dMyc transforms cells into super-competitors. Cell. 2004;117:117–29.

    Article  PubMed  CAS  Google Scholar 

  148. 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.

    Article  Google Scholar 

  149. Li W, Baker NE. Engulfment is required for cell competition. Cell. 2007;129:1215–25.

    Article  PubMed  CAS  Google Scholar 

  150. Pasciu D, Montisci S, Greco M, Doratiotto S, Pitzalis S, Pani P, et al. Aging is associated with increased clonogenic potential in rat liver in vivo. Aging Cell. 2006;5:373–7.

    Article  PubMed  CAS  Google Scholar 

  151. Menthena A, Koehler C, Sandhu JS, Yovchev M, Hurston E, Shafritz DA, Oertel M. Activin A, p15INK4b signaling, and cell competition promote stem/progenitor cell repopulation of livers in aging rats. Gastroenterology. 2011;140:1009–20.

    Article  PubMed  CAS  Google Scholar 

  152. Haruna Y, Saito K, Spaulding S, Nalesnik MA, Gerber MA. Identification of bipotential progenitor cells in human liver development. Hepatology. 1996;23:476–81.

    Article  PubMed  CAS  Google Scholar 

  153. 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.

    PubMed  CAS  Google Scholar 

  154. Lázaro CA, Croager EJ, Mitchell C, Campbell JS, Yu C, Foraker J, et al. Establishment, characterization, and long-term maintenance of cultures of human fetal hepatocytes. Hepatology. 2003;38:1095–106.

    Article  PubMed  Google Scholar 

  155. 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.

    Article  PubMed  CAS  Google Scholar 

  156. 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;54:972–9.

    Article  PubMed  CAS  Google Scholar 

  157. 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.

    Article  PubMed  CAS  Google Scholar 

  158. Schmelzer E, Wauthier E, Reid LM. The phenotypes of pluripotent human hepatic progenitors. Stem Cells. 2006;24:1852–8.

    Article  PubMed  CAS  Google Scholar 

  159. Deurholt T, ten Bloemendaal L, Chhatta AA, van Wijk AC, Weijer K, Seppen J, et al. In vitro functionality of human fetal liver cells and clonal derivatives under proliferative conditions. Cell Transplant. 2006;15:811–22.

    Article  PubMed  Google Scholar 

  160. 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.

    Article  PubMed  CAS  Google Scholar 

  161. Liu YN, Zhang J, He QH, Dai X, Shen L. Isolation and characterization of epithelial progenitor cells from human fetal liver. Hepatol Res. 2008;38:103–13.

    Article  PubMed  CAS  Google Scholar 

  162. Rao MS, Khan AA, Parveen N, Habeeb MA, Habibullah CM, Pande G. Characterization of hepatic progenitors from human fetal liver during second trimester. World J Gastroenterol. 2008;14:5730–7.

    Article  PubMed  Google Scholar 

  163. Begum S, Joshi M, Ek M, Holgersson J, Kleman MI, Sumitran-Holgersson S. Characterization and engraftment of long-term serum-free human fetal liver cell cultures. Cytotherapy. 2010;12:201–11.

    Article  PubMed  CAS  Google Scholar 

  164. Shafritz DA, Oertel M. Model systems and experimental conditions that lead to effective repopulation of the liver by transplanted cells. Int J Biochem Cell Biol. 2011;43:198–213.

    Article  PubMed  CAS  Google Scholar 

  165. Fisher RA, Strom SC. Human hepatocyte transplantation: worldwide results. Transplantation. 2006;82:441–9.

    Article  PubMed  Google Scholar 

  166. Fitzpatrick E, Mitry RR, Dhawan A. Human hepatocyte transplantation: state of the art. J Intern Med. 2009;266:339–57.

    Article  PubMed  CAS  Google Scholar 

  167. Sgroi A, Serre-Beinier V, Morel P, Bühler L. What clinical alternatives to whole liver transplantation? Current status of artificial devices and hepatocyte transplantation. Transplantation. 2009;87:457–66.

    Article  PubMed  Google Scholar 

  168. Khan AA, Shaik MV, Parveen N, Rajendraprasad A, Aleem MA, Habeeb MA, et al. Human fetal liver-derived stem cell transplantation as supportive modality in the management of end-stage decompensated liver cirrhosis. Cell Transplant. 2010;19:409–18.

    PubMed  Google Scholar 

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Acknowledgments

The author would like to thank Dr. David A. Shafritz (Department of Medicine) for his critical reading of this manuscript and fruitful discussions; and Dr. Jayanta Roy-Chowdhury (Department of Medicine) for his helpful comments.

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The author declares that he has no conflict of interest.

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  1. Division of Gastroenterology and Liver Diseases, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Ullmann 603B, Bronx, NY, 10461, USA

    Michael Oertel

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Oertel, M. Fetal liver cell transplantation as a potential alternative to whole liver transplantation?. J Gastroenterol 46, 953–965 (2011). https://doi.org/10.1007/s00535-011-0427-5

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