Adult Liver Stem Cells

Part of the Molecular Pathology Library book series (MPLB, volume 5)


The search for stem-like progenitor cells of the adult liver has been ongoing for many decades. However, as recently as 20 years ago the existence of liver cells with stem-like potential was critically questioned and not generally accepted [1, 2]. In contrast, it has long been known that tissues with high cellular turnover (like skin, intestine, and bone marrow) contain stem cells that function to maintain tissue homeostasis through continuous renewal of the cell lineage [3, 4, 5, 6, 7, 8]. Evidence for stem-like liver progenitor cells first emerged from studies of liver injury, regeneration, and carcinogenesis in rodent models. Some evidence for stem-like progenitor cells of the adult human liver has appeared in the literature during the last 20 years. Since that time, investigations into the roles that these stem-like progenitor cells play in response to hepatic injury and carcinogenesis have escalated. In addition, there is tremendous interest in pursuing the potential application of stem-like progenitor cells for treatment of liver disease through gene therapy and cell transplantation approaches [9, 10, 11, 12, 13].


Oval Cell Biliary Epithelial Cell Mature Hepatocyte Bone Marrow Progenitor Cell Liver Stem 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.


  1. 1.
    Sell S. Is there a liver stem cell? Cancer Res. 1990;50:3811–5.PubMedGoogle Scholar
  2. 2.
    Thorgeirsson SS. Hepatic stem cells. Am J Pathol. 1993;142:1331–3.PubMedGoogle Scholar
  3. 3.
    Koster MI. Making an epidermis. Ann NY Acad Sci. 2009;1170:7–10.PubMedGoogle Scholar
  4. 4.
    Casali A, Batlle E. Intestinal stem cells in mammals and Drosophila. Cell Stem Cell. 2009;4:124–7.PubMedGoogle Scholar
  5. 5.
    Garrison AP, Helmrath MA, Dekaney CM. Intestinal stem cells. J Pediatr Gastroenterol Nutr. 2009;49:2–7.PubMedGoogle Scholar
  6. 6.
    Forsberg EC, Smith-Berdan S. Parsing the niche code: the molecular mechanisms governing hematopoietic stem cell adhesion and differentiation. Haematologica. 2009;94:1477–81.PubMedGoogle Scholar
  7. 7.
    Schulz C, von Andrian UH, Massberg S. Hematopoietic stem and progenitor cells: their mobilization and homing to bone marrow and peripheral tissue. Immunol Res. 2009;44:160–8.PubMedGoogle Scholar
  8. 8.
    Amos TA, Gordon MY. Sources of human hematopoietic stem cells for transplantation – a review. Cell Transplant. 1995;4:547–69.PubMedGoogle Scholar
  9. 9.
    Dorrell C, Grompe M. Liver repair by intra- and extrahepatic progenitors. Stem Cell Rev. 2005;1:61–4.PubMedGoogle Scholar
  10. 10.
    Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology. 2004;39:1477–87.PubMedGoogle Scholar
  11. 11.
    Oertel M, Shafritz DA. Stem cells, cell transplantation and liver repopulation. Biochim Biophys Acta. 2008;1782:61–74.PubMedGoogle Scholar
  12. 12.
    Grompe M. Principles of therapeutic liver repopulation. J Inherit Metab Dis. 2006;29:421–5.PubMedGoogle Scholar
  13. 13.
    Santoni-Rugiu E, Jelnes P, Thorgeirsson SS, et al. Progenitor cells in liver regeneration: molecular responses controlling their activation and expansion. APMIS. 2005;113:876–902.PubMedGoogle Scholar
  14. 14.
    Robey PG. Stem cells near the century mark. J Clin Invest. 2000;105:1489–91.PubMedGoogle Scholar
  15. 15.
    Marshak DR, Gottlieb D, Gardner RL. Introduction: stem cell biology. In: Marshak DR, Gardner RL, Gottlieb D, editors. Stem cell biology. Cold Spring Harbor: Cold Spring Harbor Press; 2001. p. 1–16.Google Scholar
  16. 16.
    Grisham JW, Coleman WB. Neoformation of liver epithelial cells: progenitor cells, stem cells, and phenotypic transitions. Gastroenterology. 1996;110:1311–3.PubMedGoogle Scholar
  17. 17.
    Coleman WB, Grisham JW. Epithelial stem-like cells of the rodent liver. In: Strain AJ, Diehl AM, editors. Liver growth and repair. London: Chapman and Hall; 1998. p. 50–99.Google Scholar
  18. 18.
    Wulf GG, Jackson KA, Goodell MA. Somatic stem cell plasticity: current evidence and emerging concepts. Exp Hematol. 2001;29:1361–70.PubMedGoogle Scholar
  19. 19.
    D’Amour KA, Gage FH. Are somatic stem cells pluripotent or lineage-restricted? Nat Med. 2002;8:213–4.PubMedGoogle Scholar
  20. 20.
    Strain AJ. Changing blood into liver: adding further intrigue to the hepatic stem cell story. Hepatology. 1999;30:1105–7.PubMedGoogle Scholar
  21. 21.
    Zhou P, Wirthlin L, McGee J, et al. Contribution of human hematopoietic stem cells to liver repair. Semin Immunopathol. 2009;31:411–9.PubMedGoogle Scholar
  22. 22.
    Anderson DJ, Gage FH, Weissman IL. Can stem cells cross lineage boundaries? Nat Med. 2001;7:393–5.PubMedGoogle Scholar
  23. 23.
    Tsao MS, Smith JD, Nelson KG, et al. A diploid epithelial cell line from normal adult rat liver with phenotypic properties of ‘oval’ cells. Exp Cell Res. 1984;154:38–52.PubMedGoogle Scholar
  24. 24.
    Grisham JW, Thorgeirsson SS. Liver stem cells. In: Potten CS, editor. Stem cells. London: Academic Press; 1997. p. 233–82.Google Scholar
  25. 25.
    MacCallum WG. Regenerative changes in the liver after acute yellow atrophy. Johns Hopkins Hosp Report. 1902;10:375–9.Google Scholar
  26. 26.
    MacCallum WG. Regenerative changes in cirrhosis of the liver. J Am Med Asso. 1904;43:649–54.Google Scholar
  27. 27.
    Muir R. On proliferation of the cells of the liver. J Pathol Bacteriol. 1908;12:287–305.Google Scholar
  28. 28.
    Milne L. The histology of liver tissue regeneration. J Pathol Bacteriol. 1909;13:127–60.Google Scholar
  29. 29.
    Price JM, Harman JW, Miller EC, et al. Progressive microscopic alterations in the livers of rats fed the hepatic carcinogens 3′-methyl-4-dimethylaminoazobenzene and 4′-fluoro-4-dimethylaminoazobenzene. Cancer Res. 1952;12:192–200.PubMedGoogle Scholar
  30. 30.
    Firminger HI. Histopathology of carcinogenesis and tumors of the liver in rats. J Natl Cancer Inst. 1955;15:1427–42.PubMedGoogle Scholar
  31. 31.
    Wilson JW, Leduc EH. Role of cholangioles in restoration of the liver of the mouse after dietary injury. J Pathol Bacteriol. 1958;76:441–9.PubMedGoogle Scholar
  32. 32.
    Sell S. Liver stem cells. Mod Pathol. 1994;7:105–12.PubMedGoogle Scholar
  33. 33.
    Fausto N. Hepatocyte differentiation and liver progenitor cells. Curr Opin Cell Biol. 1990;2:1036–42.PubMedGoogle Scholar
  34. 34.
    Aterman K. The stem cells of the liver – a selective review. J Cancer Res Clin Oncol. 1992;118:87–115.PubMedGoogle Scholar
  35. 35.
    Fausto N. Liver stem cells. In: Arias IM et al., editors. The liver: biology and pathobiology. New York: Raven Press; 2004. p. 1501–18.Google Scholar
  36. 36.
    Golding M, Sarraf C, Lalani EN, et al. Reactive biliary epithelium: the product of a pluripotential stem cell compartment? Hum Pathol. 1996;27:872–84.PubMedGoogle Scholar
  37. 37.
    Fausto N. Liver stem cells. In: Arias IM et al., editors. The liver: biology and pathobiology. New York: Raven Press; 1994. p. 1501–18.Google Scholar
  38. 38.
    Grisham JW. Migration of hepatocytes along hepatic plates and stem cell-fed hepatocyte lineages. Am J Pathol. 1994;144:849–54.PubMedGoogle Scholar
  39. 39.
    Potten CS, Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development. 1990;110:1001–20.PubMedGoogle Scholar
  40. 40.
    Potten CS, Morris RJ. Epithelial stem cells in vivo. J Cell Sci Suppl. 1988;10:45–62.PubMedGoogle Scholar
  41. 41.
    van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol. 2009;71:241–60.PubMedGoogle Scholar
  42. 42.
    Cotsarelis G, Cheng SZ, Dong G, et al. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell. 1989;57:201–9.PubMedGoogle Scholar
  43. 43.
    Hall PA, Watt FM. Stem cells: the generation and maintenance of cellular diversity. Development. 1989;106:619–33.PubMedGoogle Scholar
  44. 44.
    Abbas O, Mahalingam M. Epidermal stem cells: practical perspectives and potential uses. Br J Dermatol. 2009;161:228–36.PubMedGoogle Scholar
  45. 45.
    Weissman IL, Shizuru JA. The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases. Blood. 2008;112:3543–53.PubMedGoogle Scholar
  46. 46.
    Majeti R, Park CY, Weissman IL. Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood. Cell Stem Cell. 2007;1:635–45.PubMedGoogle Scholar
  47. 47.
    Grisham JW. Cell types in long-term propagable cultures of rat liver. Ann NY Acad Sci. 1980;349:128–37.PubMedGoogle Scholar
  48. 48.
    Grisham JW. Cell types in rat liver cultures: their identification and isolation. Mol Cell Biochem. 1983;53–54:23–33.PubMedGoogle Scholar
  49. 49.
    Coleman WB, Grisham JW, Malouf NN. Adult liver stem cells. In: Turksen K, editor. Adult stem cells. Totowa, NJ: Humana Press; 2004. p. 101–48.Google Scholar
  50. 50.
    Alison MR. Characterization of the differentiation capacity of rat-derived hepatic stem cells. Semin Liver Dis. 2003;23:325–36.PubMedGoogle Scholar
  51. 51.
    Alison MR, Vig P, Russo F, et al. Hepatic stem cells: from inside and outside the liver? Cell Prolif. 2004;37:1–21.PubMedGoogle Scholar
  52. 52.
    Alison M, Sarraf C. Hepatic stem cells. J Hepatol. 1998;29:676–82.PubMedGoogle Scholar
  53. 53.
    Gaudio E, Carpino G, Cardinale V, et al. New insights into liver stem cells. Dig Liver Dis. 2009;41:455–62.PubMedGoogle Scholar
  54. 54.
    Mancino MG, Carpino G, Onori P, et al. Hepatic “stem” cells: state of the art. Ital J Anat Embryol. 2007;112:93–109.PubMedGoogle Scholar
  55. 55.
    Sharma AD, Cantz T, Manns MP, et al. The role of stem cells in physiology, pathophysiology, and therapy of the liver. Stem Cell Rev. 2006;2:51–8.PubMedGoogle Scholar
  56. 56.
    Walkup MH, Gerber DA. Hepatic stem cells: in search of. Stem Cells. 2006;24:1833–40.PubMedGoogle Scholar
  57. 57.
    Sell S. The role of progenitor cells in repair of liver injury and in liver transplantation. Wound Repair Regen. 2001;9:467–82.PubMedGoogle Scholar
  58. 58.
    Slack JM. Stem cells in epithelial tissues. Science. 2000;287:1431–3.PubMedGoogle Scholar
  59. 59.
    Johansson CB, Momma S, Clarke DL, et al. Identification of a neural stem cell in the adult mammalian central nervous system. Cell. 1999;96:25–34.PubMedGoogle Scholar
  60. 60.
    Johansson CB, Svensson M, Wallstedt L, et al. Neural stem cells in the adult human brain. Exp Cell Res. 1999;253:733–6.PubMedGoogle Scholar
  61. 61.
    Morrison SJ, White PM, Zock C, et al. Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. Cell. 1999;96:737–49.PubMedGoogle Scholar
  62. 62.
    Le Douarin NM, Calloni GW, Dupin E. The stem cells of the neural crest. Cell Cycle. 2008;7:1013–9.PubMedGoogle Scholar
  63. 63.
    Nagoshi N, Shibata S, Nakamura M, et al. Neural crest-derived stem cells display a wide variety of characteristics. J Cell Biochem. 2009;107:1046–52.PubMedGoogle Scholar
  64. 64.
    Watt FM. Epidermal stem cells. In: Gardner RL, Gottlieb D, Marshak DR, editors. Stem cell biology. Cold Spring Harbor: Cold Spring Harbor Press; 2001. p. 439–53.Google Scholar
  65. 65.
    Winton DJ. Stem cells in the epithelium of the small intestine and colon. In: Gardner RL, Gottlieb D, Marshak DR, editors. Stem cell biology. Cold Spring Harbor: Cold Spring Harbor Press; 2001. p. 515–36.Google Scholar
  66. 66.
    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
  67. 67.
    Tatematsu M, Ho RH, Kaku T, et al. Studies on the proliferation and fate of oval cells in the liver of rats treated with 2-acetylaminofluorene and partial hepatectomy. Am J Pathol. 1984;114:418–30.PubMedGoogle Scholar
  68. 68.
    Tatematsu M, Kaku T, Medline A, et al. Intestinal metaplasia as a common option of oval cells in relation to cholangiofibrosis in liver of rats exposed to 2-acetylaminofluorene. Lab Invest. 1985;52:354–62.PubMedGoogle Scholar
  69. 69.
    Gordon GJ, Coleman WB, Hixson DC, et al. Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response. Am J Pathol. 2000;156:607–19.PubMedGoogle Scholar
  70. 70.
    Michalopoulos GK. Liver regeneration: molecular mechanisms of growth control. FASEB J. 1990;4:176–87.PubMedGoogle Scholar
  71. 71.
    Michalopoulos GK. Liver regeneration. J Cell Physiol. 2007;213:286–300.PubMedGoogle Scholar
  72. 72.
    Michalopoulos GK, DeFrances MC. Liver regeneration. Science. 1997;276:60–6.PubMedGoogle Scholar
  73. 73.
    Fausto N. Liver regeneration. J Hepatol. 2000;32:19–31.PubMedGoogle Scholar
  74. 74.
    Fausto N, Campbell JS. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech Dev. 2003;120:117–30.PubMedGoogle Scholar
  75. 75.
    Klinman NR, Erslev AJ. Cellular response to partial hepatectomy. Proc Soc Exp Biol Med. 1963;112:338–40.PubMedGoogle Scholar
  76. 76.
    Dabeva MD, Alpini G, Hurston E, et al. Models for hepatic progenitor cell activation. Proc Soc Exp Biol Med. 1993;204:242–52.PubMedGoogle Scholar
  77. 77.
    Grisham JW. Cellular proliferation in the liver. Recent Results Cancer Res. 1969;17:28–43.Google Scholar
  78. 78.
    Fabrikant JI. Rate of cell proliferation in the regenerating liver. Br J Radiol. 1968;41:71.PubMedGoogle Scholar
  79. 79.
    Fabrikant JI. The kinetics of cellular proliferation in regenerating liver. J Cell Biol. 1968;36:551–65.PubMedGoogle Scholar
  80. 80.
    Marucci L, Baroni GS, Mancini R, et al. Cell proliferation following extrahepatic biliary obstruction. Evaluation by immunohistochemical methods. J Hepatol. 1993;17:163–9.PubMedGoogle Scholar
  81. 81.
    Polimeno L, Azzarone A, Zeng QH, et al. Cell proliferation and oncogene expression after bile duct ligation in the rat: evidence of a specific growth effect on bile duct cells. Hepatology. 1995;21:1070–8.PubMedGoogle Scholar
  82. 82.
    Fabrikant JI. Size of proliferating pools in regenerating liver. Exp Cell Res. 1969;55:277–9.PubMedGoogle Scholar
  83. 83.
    Stocker E, Heine WD. Regeneration of liver parenchyma under normal and pathological conditions. Beitr Pathol. 1971;144:400–8.PubMedGoogle Scholar
  84. 84.
    Simpson GE, Finckh ES. The pattern of regeneration of rat liver after repeated partial hepatectomies. J Pathol Bacteriol. 1963;86:361–70.PubMedGoogle Scholar
  85. 85.
    Sandgren EP, Palmiter RD, Heckel JL, et al. Complete hepatic regeneration after somatic deletion of an albumin-plasminogen activator transgene. Cell. 1991;66:245–56.PubMedGoogle Scholar
  86. 86.
    Rhim JA, Sandgren EP, Degen JL, et al. Replacement of diseased mouse liver by hepatic cell transplantation. Science. 1994;263:1149–52.PubMedGoogle Scholar
  87. 87.
    Overturf K, Al-Dhalimy M, Tanguay R, 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
  88. 88.
    Grompe M, al-Dhalimy M, Finegold M, et al. Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev. 1993;7:2298–307.PubMedGoogle Scholar
  89. 89.
    Overturf K, al-Dhalimy M, Ou CN, et al. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol. 1997;151:1273–80.PubMedGoogle Scholar
  90. 90.
    Overturf K, Al-Dhalimy M, Finegold M, et al. The repopulation potential of hepatocyte populations differing in size and prior mitotic expansion. Am J Pathol. 1999;155:2135–43.PubMedGoogle Scholar
  91. 91.
    Azuma H, Paulk N, Ranade A, et al. Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol. 2007;25:903–10.PubMedGoogle Scholar
  92. 92.
    Laconi E, Oren R, Mukhopadhyay DK, 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
  93. 93.
    Dabeva MD, Laconi E, Oren R, et al. Liver regeneration and alpha-fetoprotein messenger RNA expression in the retrorsine model for hepatocyte transplantation. Cancer Res. 1998;58:5825–34.PubMedGoogle Scholar
  94. 94.
    Oren R, Dabeva MD, Karnezis AN, et al. Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes. Hepatology. 1999;30:903–13.PubMedGoogle Scholar
  95. 95.
    Jago MV. The development of the hepatic megalocytosis of chronic pyrrolizidine alkaloid poisoning. Am J Pathol. 1969;56:405–21.PubMedGoogle Scholar
  96. 96.
    Gordon GJ, Coleman WB, Grisham JW. Temporal analysis of hepatocyte differentiation by small hepatocyte-like progenitor cells during liver regeneration in retrorsine-exposed rats. Am J Pathol. 2000;157:771–86.PubMedGoogle Scholar
  97. 97.
    Vig P, Russo FP, Edwards RJ, et al. The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice. Hepatology. 2006;43:316–24.PubMedGoogle Scholar
  98. 98.
    Avril A, Pichard V, Bralet MP, et al. Mature hepatocytes are the source of small hepatocyte-like progenitor cells in the retrorsine model of liver injury. J Hepatol. 2004;41:737–43.PubMedGoogle Scholar
  99. 99.
    Pichard V, Ferry N. Origin of small hepatocyte-like progenitor in retrorsine-treated rats. J Hepatol. 2008;48:368–9.PubMedGoogle Scholar
  100. 100.
    Pichard V, Aubert D, Ferry N. Direct in vivo cell lineage analysis in the retrorsine and 2AAF models of liver injury after genetic labeling in adult and newborn rats. PLoS One. 2009;4:e7267.PubMedGoogle Scholar
  101. 101.
    Best DH, Coleman WB. Cells of origin of small hepatocyte-like progenitor cells in the retrorsine model of rat liver injury and regeneration. J Hepatol. 2008;48:369–71.Google Scholar
  102. 102.
    Coleman WB, Best DH. Cellular responses in experimental liver injury: Possible cellular origins of regenerative stem-like progenitor cells. Hepatology. 2005;41:1173–6.Google Scholar
  103. 103.
    Best DH, Coleman WB. Treatment with 2-AAF blocks the small hepatocyte-like progenitor cell response in retrorsine-exposed rats. J Hepatol. 2007;46:1055–63.PubMedGoogle Scholar
  104. 104.
    Best DH, Coleman WB. Bile duct destruction by 4, 4′-diaminodiphenylmethane does not block the small hepatocyte-like progenitor cell response in retrorsine-exposed rats. Hepatology. 2007;46(5):1611–9.PubMedGoogle Scholar
  105. 105.
    Brill S, Holst P, Sigal S, et al. Hepatic progenitor populations in embryonic, neonatal, and adult liver. Proc Soc Exp Biol Med. 1993;204:261–9.PubMedGoogle Scholar
  106. 106.
    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.PubMedGoogle Scholar
  107. 107.
    He XY, Smith GJ, Enno A, et al. Short-term diethylnitrosamine-induced oval cell responses in three strains of mice. Pathology. 1994;26:154–60.PubMedGoogle Scholar
  108. 108.
    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
  109. 109.
    Bennoun M, Rissel M, Engelhardt N, et al. Oval cell proliferation in early stages of hepatocarcinogenesis in simian virus 40 large T transgenic mice. Am J Pathol. 1993;143:1326–36.PubMedGoogle Scholar
  110. 110.
    Richards WG, Yoder BK, Isfort RJ, et al. Oval cell proliferation associated with the murine insertional mutation TgN737Rpw. Am J Pathol. 1996;149:1919–30.PubMedGoogle Scholar
  111. 111.
    Dunsford HA, Sell S, Chisari FV. Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice. Cancer Res. 1990;50:3400–7.PubMedGoogle Scholar
  112. 112.
    Wang X, Foster M, Al-Dhalimy M, et al. The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci U S A. 2003;100 Suppl 1:11881–8.PubMedGoogle Scholar
  113. 113.
    Sell S, Salman J. Light- and electron-microscopic autoradiographic analysis of proliferating cells during the early stages of chemical hepatocarcinogenesis in the rat induced by feeding N-2-fluorenylacetamide in a choline-deficient diet. Am J Pathol. 1984;114:287–300.PubMedGoogle Scholar
  114. 114.
    Yaswen P, Hayner NT, Fausto N. Isolation of oval cells by centrifugal elutriation and comparison with other cell types purified from normal and preneoplastic livers. Cancer Res. 1984;44:324–31.PubMedGoogle Scholar
  115. 115.
    Fausto N, Lemire JM, Shiojri N. Oval cells in liver carcinogenesis: cell lineages in hepatic development and the identification of faculative stem cells in normal liver. In: Sirica AE, editor. The role of cell types in carcinogenesis. Boca Raton: CRC Press; 1992. p. 89–108.Google Scholar
  116. 116.
    Grisham JW, Hartroft WS. Morphologic identification by electron microscopy of “oval” cells in experimental hepatic degeneration. Lab Invest. 1961;10:317–32.PubMedGoogle Scholar
  117. 117.
    Lenzi R, Liu MH, Tarsetti F, et al. Histogenesis of bile duct-like cells proliferating during ethionine hepatocarcinogenesis. Evidence for a biliary epithelial nature of oval cells. Lab Invest. 1992;66:390–402.PubMedGoogle Scholar
  118. 118.
    Sarraf C, Lalani EN, Golding M, et al. Cell behavior in the acetylaminofluorene-treated regenerating rat liver. Light and electron microscopic observations. Am J Pathol. 1994;145:1114–26.PubMedGoogle Scholar
  119. 119.
    Inaoka Y. Significance of the so-called oval cell proliferation during azo-dye hepatocarcinogenesis. Gann. 1967;58:355–66.PubMedGoogle Scholar
  120. 120.
    Dunsford HA, Maset R, Salman J, et al. Connection of ductlike structures induced by a chemical hepatocarcinogen to portal bile ducts in the rat liver detected by injection of bile ducts with a pigmented barium gelatin medium. Am J Pathol. 1985;118:218–24.PubMedGoogle Scholar
  121. 121.
    Makino Y, Yamamoto K, Tsuji T. Three-dimensional arrangement of ductular structures formed by oval cells during hepatocarcinogenesis. Acta Med Okayama. 1988;42:143–50.PubMedGoogle Scholar
  122. 122.
    Evarts RP, Nagy P, Marsden E, et al. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis. 1987;8:1737–40.PubMedGoogle Scholar
  123. 123.
    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
  124. 124.
    Evarts RP, Nagy P, Nakatsukasa H, et al. In vivo differentiation of rat liver oval cells into hepatocytes. Cancer Res. 1989;49:1541–7.PubMedGoogle Scholar
  125. 125.
    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
  126. 126.
    Golding M, Sarraf CE, Lalani EN, et al. Oval cell differentiation into hepatocytes in the acetylaminofluorene-treated regenerating rat liver. Hepatology. 1995;22:1243–53.PubMedGoogle Scholar
  127. 127.
    Alison MR, Golding M, Sarraf CE, et al. Liver damage in the rat induces hepatocyte stem cells from biliary epithelial cells. Gastroenterology. 1996;110:1182–90.PubMedGoogle Scholar
  128. 128.
    Orkin SH. Hematopoietic stem cells: molecular diversification and developmental interrelationships. In: Gardner RL, Gottlieb D, Marshak DR, editors. Stem cell biology. Cold Spring Harbor: Cold Spring Harbor Press; 2001. p. 289–306.Google Scholar
  129. 129.
    Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701–5.PubMedGoogle Scholar
  130. 130.
    Ferrari G, Cusella-De Angelis G, Coletta M, et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279:1528–30.PubMedGoogle Scholar
  131. 131.
    Gussoni E, Soneoka Y, Strickland CD, et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature. 1999;401:390–4.PubMedGoogle Scholar
  132. 132.
    Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A. 1999;96:10711–6.PubMedGoogle Scholar
  133. 133.
    Brazelton TR, Rossi FM, Keshet GI, et al. From marrow to brain: expression of neuronal phenotypes in adult mice. Science. 2000;290:1775–9.PubMedGoogle Scholar
  134. 134.
    Mezey E, Chandross KJ, Harta G, et al. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000;290:1779–82.PubMedGoogle Scholar
  135. 135.
    Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001;105:369–77.PubMedGoogle Scholar
  136. 136.
    Petersen BE, Bowen WC, Patrene KD, et al. Bone marrow as a potential source of hepatic oval cells. Science. 1999;284:1168–70.PubMedGoogle Scholar
  137. 137.
    Theise ND, Badve S, Saxena R, et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology. 2000;31:235–40.PubMedGoogle Scholar
  138. 138.
    Theise ND, Nimmakayalu M, Gardner R, et al. Liver from bone marrow in humans. Hepatology. 2000;32:11–6.PubMedGoogle Scholar
  139. 139.
    Alison MR, Poulsom R, Jeffery R, et al. Hepatocytes from non-hepatic adult stem cells. Nature. 2000;406:257.PubMedGoogle Scholar
  140. 140.
    Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med. 2000;6:1229–34.PubMedGoogle Scholar
  141. 141.
    Wang X, Montini E, Al-Dhalimy M, et al. Kinetics of liver repopulation after bone marrow transplantation. Am J Pathol. 2002;161:565–74.PubMedGoogle Scholar
  142. 142.
    Thorgeirsson SS, Grisham JW. Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology. 2006;43:2–8.PubMedGoogle Scholar
  143. 143.
    Mallet VO, Mitchell C, Mezey E, et al. Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo. Hepatology. 2002;35:799–804.PubMedGoogle Scholar
  144. 144.
    Gao Z, McAlister VC, Williams GM. Repopulation of liver endothelium by bone-marrow-derived cells. Lancet. 2001;357:932–3.PubMedGoogle Scholar
  145. 145.
    Wagers AJ, Sherwood RI, Christensen JL, et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002;297:2256–9.PubMedGoogle Scholar
  146. 146.
    Reyes M, Verfaillie CM. Characterization of multipotent adult progenitor cells, a subpopulation of mesenchymal stem cells. Ann NY Acad Sci. 2001;938:231–3.PubMedGoogle Scholar
  147. 147.
    Reyes M, Lund T, Lenvik T, et al. Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood. 2001;98:2615–25.PubMedGoogle Scholar
  148. 148.
    Schwartz RE, Reyes M, Koodie L, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest. 2002;109:1291–302.PubMedGoogle Scholar
  149. 149.
    Rao MS, Dwivedi RS, Subbarao V, et al. Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation. Biochem Biophys Res Commun. 1988;156:131–6.PubMedGoogle Scholar
  150. 150.
    Rao MS, Dwivedi RS, Yeldandi AV, et al. Role of periductal and ductular epithelial cells of the adult rat pancreas in pancreatic hepatocyte lineage. A change in the differentiation commitment. Am J Pathol. 1989;134:1069–86.PubMedGoogle Scholar
  151. 151.
    Bisgaard HC, Thorgeirsson SS. Evidence for a common cell of origin for primitive epithelial cells isolated from rat liver and pancreas. J Cell Physiol. 1991;147:333–43.PubMedGoogle Scholar
  152. 152.
    Dabeva MD, Hwang SG, Vasa SR, et al. Differentiation of pancreatic epithelial progenitor cells into hepatocytes following transplantation into rat liver. Proc Natl Acad Sci U S A. 1997;94:7356–61.PubMedGoogle Scholar
  153. 153.
    Wang X, Al-Dhalimy M, Lagasse E, et al. Liver repopulation and correction of metabolic liver disease by transplanted adult mouse pancreatic cells. Am J Pathol. 2001;158:571–9.PubMedGoogle Scholar
  154. 154.
    Chen JR, Tsao MS, Duguid WP. Hepatocytic differentiation of cultured rat pancreatic ductal epithelial cells after in vivo implantation. Am J Pathol. 1995;147:707–17.PubMedGoogle Scholar
  155. 155.
    Gage FH. Mammalian neural stem cells. Science. 2000;287:1433–8.PubMedGoogle Scholar
  156. 156.
    Gage FH, Coates PW, Palmer TD, et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci U S A. 1995;92:11879–83.PubMedGoogle Scholar
  157. 157.
    Bjornson CR, Rietze RL, Reynolds BA, et al. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science. 1999;283:534–7.PubMedGoogle Scholar
  158. 158.
    Clarke DL, Johansson CB, Wilbertz J, et al. Generalized potential of adult neural stem cells. Science. 2000;288:1660–3.PubMedGoogle Scholar
  159. 159.
    Sell S. Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury. Hepatology. 1998;27:317–31.PubMedGoogle Scholar
  160. 160.
    Van Den Heuvel MC, Slooff MJ, Visser L, et al. Expression of anti-OV6 antibody and anti-N-CAM antibody along the biliary line of normal and diseased human livers. Hepatology. 2001;33:1387–93.Google Scholar
  161. 161.
    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
  162. 162.
    Korbling M, Katz RL, Khanna A, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med. 2002;346:738–46.PubMedGoogle Scholar
  163. 163.
    Fogt F, Beyser KH, Poremba C, et al. Recipient-derived hepatocytes in liver transplants: a rare event in sex-mismatched transplants. Hepatology. 2002;36:173–6.PubMedGoogle Scholar
  164. 164.
    Alpini G, Phillips JO, Vroman B, et al. Recent advances in the isolation of liver cells. Hepatology. 1994;20:494–514.PubMedGoogle Scholar
  165. 165.
    Joplin R. Isolation and culture of biliary epithelial cells. Gut. 1994;35:875–8.PubMedGoogle Scholar
  166. 166.
    Grisham JW, Thal SB, Nagel AE. Cellular derivation of continuously cultured epithelial cells from normal rat liver. In: Gerschenson LE, Thompson EB, editors. Gene expression and carcinogenesis in cultured liver. New York: Academic Press; 1975. p. 1–23.Google Scholar
  167. 167.
    Grisham JW, Coleman WB, Smith GJ. Isolation, culture, and transplantation of rat hepatocytic precursor (stem-like) cells. Proc Soc Exp Biol Med. 1993;204:270–9.PubMedGoogle Scholar
  168. 168.
    Alexander RW, Grisham JW. Explant culture of rat liver. I. Method, morphology, and cytogenesis. Lab Invest. 1970;22:50–62.PubMedGoogle Scholar
  169. 169.
    Seglen PO. Preparation of isolated rat liver cells. Methods Cell Biol. 1976;13:29–83.PubMedGoogle Scholar
  170. 170.
    Berry MN, Friend DS. High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol. 1969;43:506–20.PubMedGoogle Scholar
  171. 171.
    Williams GM. Primary and long-term culture of adult rat liver epithelial cells. Methods Cell Biol. 1976;14:357–64.PubMedGoogle Scholar
  172. 172.
    Mills DM, Zucker-Franklin D. Electron microscopic study of isolated Kupffer cells. Am J Pathol. 1969;54:147–66.PubMedGoogle Scholar
  173. 173.
    Emeis JJ, Planque B. Heterogeneity of cells isolated from rat liver by pronase digestion: ultrastructure, cytochemistry and cell culture. J Reticuloendothel Soc. 1976;20:11–29.PubMedGoogle Scholar
  174. 174.
    Furukawa K, Shimada T, England P, et al. Enrichment and characterization of clonogenic epithelial cells from adult rat liver and initiation of epithelial cell strains. In Vitro Cell Dev Biol. 1987;23:339–48.PubMedGoogle Scholar
  175. 175.
    Fausto N, Thompson HL, Braun L. Purification and culture of oval cells from rat liver. In: Pretlow TR, Pretlow TG, editors. Cell separation methods and selected applications. Orlando, FL: Academic Press; 1987. p. 45–77.Google Scholar
  176. 176.
    Radaeva S, Steinberg P. Phenotype and differentiation patterns of the oval cell lines OC/CDE 6 and OC/CDE 22 derived from the livers of carcinogen-treated rats. Cancer Res. 1995;55:1028–38.PubMedGoogle Scholar
  177. 177.
    Pack R, Heck R, Dienes HP, et al. Isolation, biochemical characterization, long-term culture, and phenotype modulation of oval cells from carcinogen-fed rats. Exp Cell Res. 1993;204:198–209.PubMedGoogle Scholar
  178. 178.
    Plenat F, Braun L, Fausto N. Demonstration of glucose-6-phosphatase and peroxisomal catalase activity by ultrastructural cytochemistry in oval cells from livers of carcinogen-treated rats. Am J Pathol. 1988;130:91–102.PubMedGoogle Scholar
  179. 179.
    Hayner NT, Braun L, Yaswen P, et al. Isozyme profiles of oval cells, parenchymal cells, and biliary cells isolated by centrifugal elutriation from normal and preneoplastic livers. Cancer Res. 1984;44:332–8.PubMedGoogle Scholar
  180. 180.
    Nussler AK, Vergani G, Gollin SM, et al. Isolation and characterization of a human hepatic epithelial-like cell line (AKN-1) from a normal liver. In Vitro Cell Dev Biol Anim. 1999;35:190–7.PubMedGoogle Scholar
  181. 181.
    Coleman WB, Wennerberg AE, Smith GJ, et al. Regulation of the differentiation of diploid and some aneuploid rat liver epithelial (stemlike) cells by the hepatic microenvironment. Am J Pathol. 1993;142:1373–82.PubMedGoogle Scholar
  182. 182.
    Coleman WB, McCullough KD, Esch GL, 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
  183. 183.
    Coleman WB, Butz GM, Howell JA, et al. Transplantation and differentiation of rat liver epithelial stem-like cells. In: Gupta S et al., editors. Hepatocyte transplantation. Dordrecht, The Netherlands: Kluwer Academic Publishers; 2002.Google Scholar
  184. 184.
    Price J, Turner D, Cepko C. Lineage analysis in the vertebrate nervous system by retrovirus-mediated gene transfer. Proc Natl Acad Sci U S A. 1987;84:156–60.PubMedGoogle Scholar
  185. 185.
    Watanabe Y, Kojima T, Fujimoto Y. Deficiency of membrane-bound dipeptidyl aminopeptidase IV in a certain rat strain. Experientia. 1987;43:400–1.PubMedGoogle Scholar
  186. 186.
    Thompson NL, Hixson DC, Callanan H, 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;273(Pt 3):497–502.PubMedGoogle Scholar
  187. 187.
    Hong W, Doyle D. cDNA cloning for a bile canaliculus domain-specific membrane glycoprotein of rat hepatocytes. Proc Natl Acad Sci U S A. 1987;84:7962–6.PubMedGoogle Scholar
  188. 188.
    Fukui Y, Yamamoto A, Kyoden T, et al. Quantitative immunogold localization of dipeptidyl peptidase IV (DPP IV) in rat liver cells. Cell Struct Funct. 1990;15:117–25.PubMedGoogle Scholar
  189. 189.
    Nagase S, Shimamune K, Shumiya S. Albumin-deficient rat mutant. Science. 1979;205:590–1.PubMedGoogle Scholar
  190. 190.
    Ogawa K, Ohta T, Inagaki M, et al. Identification of F344 rat hepatocytes transplanted within the liver of congenic analbuminemic rats by the polymerase chain reaction. Transplantation. 1993;56:9–15.PubMedGoogle Scholar
  191. 191.
    Germain L, Noel M, Gourdeau H, et al. Promotion of growth and differentiation of rat ductular oval cells in primary culture. Cancer Res. 1988;48:368–78.PubMedGoogle Scholar
  192. 192.
    Lazaro CA, Rhim JA, Yamada Y, et al. Generation of hepatocytes from oval cell precursors in culture. Cancer Res. 1998;58:5514–22.PubMedGoogle Scholar
  193. 193.
    McMahon JB, Richards WL, del Campo AA, et al. Differential effects of transforming growth factor-beta on proliferation of normal and malignant rat liver epithelial cells in culture. Cancer Res. 1986;46:4665–71.PubMedGoogle Scholar
  194. 194.
    Thorgeirsson SS, Grisham JW. Overview of recent experimental studies on liver stem cells. Semin Liver Dis. 2003;23:303–12.PubMedGoogle Scholar
  195. 195.
    Coleman WB, Smith GJ, Grisham JW. Development of dexamethasone-inducible tyrosine aminotransferase activity in WB-F344 rat liver epithelial stemlike cells cultured in the presence of sodium butyrate. J Cell Physiol. 1994;161:463–9.PubMedGoogle Scholar
  196. 196.
    Ernest MJ, Chen CL, Feigelson P. Induction of tyrosine aminotransferase synthesis in isolated liver cell suspensions. Absolute dependence of induction on glucocorticoids and glucagon or cyclic AMP. J Biol Chem. 1977;252:6783–91.PubMedGoogle Scholar
  197. 197.
    Ho KK, Cake MH, Yeoh GC, et al. Insulin antagonism of glucocorticoid induction of tyrosine aminotransferase in cultured foetal hepatocytes. Eur J Biochem. 1981;118:137–42.PubMedGoogle Scholar
  198. 198.
    Couchie D, Holic N, Chobert MN, et al. In vitro differentiation of WB-F344 rat liver epithelial cells into the biliary lineage. Differentiation. 2002;69:209–15.PubMedGoogle Scholar
  199. 199.
    Yao H, Jia Y, Zhou J, et al. RhoA promotes differentiation of WB-F344 cells into the biliary lineage. Differentiation. 2009;77:154–61.PubMedGoogle Scholar
  200. 200.
    Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274:1379–83.PubMedGoogle Scholar
  201. 201.
    Sakamoto T, Liu Z, Murase N, et al. Mitosis and apoptosis in the liver of interleukin-6-deficient mice after partial hepatectomy. Hepatology. 1999;29:403–11.PubMedGoogle Scholar
  202. 202.
    Nagy P, Kiss A, Schnur J, et al. Dexamethasone inhibits the proliferation of hepatocytes and oval cells but not bile duct cells in rat liver. Hepatology. 1998;28:423–9.PubMedGoogle Scholar
  203. 203.
    Best DH, Butz GM, Coleman WB. Cytokine-dependent activation of small hepatocyte-like progenitor cells in retrorsine-induced rat liver injury. Exp Mol Pathol. 2010;88:7–14.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of North Carolina School of MedicineChapel HillUSA

Personalised recommendations