1932

Abstract

The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent liver progenitor cells are theorized to be activated as an additional tier of liver repair. However, the existence, origin, fate, activation, and contribution to regeneration of liver progenitor cells is hotly debated, especially since hepatocytes and biliary epithelial cells themselves may serve as facultative stem cells for one another during severe liver injury. Here, we discuss the evidence both supporting and refuting the existence of liver progenitor cells in a variety of experimental models. We also debate the validity of developing therapies harnessing the capabilities of these cells as potential treatments for patients with severe and chronic liver diseases.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathmechdis-012419-032824
2020-01-24
2024-06-24
Loading full text...

Full text loading...

/deliver/fulltext/pathol/15/1/annurev-pathmechdis-012419-032824.html?itemId=/content/journals/10.1146/annurev-pathmechdis-012419-032824&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Stoick-Cooper CL, Moon RT, Weidinger G 2007. Advances in signaling in vertebrate regeneration as a prelude to regenerative medicine. Genes Dev 21:1292–315
    [Google Scholar]
  2. 2. 
    Cordero-Espinoza L, Huch M. 2018. The balancing act of the liver: tissue regeneration versus fibrosis. J. Clin. Investig. 128:85–96
    [Google Scholar]
  3. 3. 
    Vivien CJ, Hudson JE, Porrello ER 2016. Evolution, comparative biology and ontogeny of vertebrate heart regeneration. NPJ Regen. Med. 1:16012
    [Google Scholar]
  4. 4. 
    Ferretti P, Zhang F, O'Neill P 2003. Changes in spinal cord regenerative ability through phylogenesis and development: lessons to be learnt. Dev. Dyn. 226:245–56
    [Google Scholar]
  5. 5. 
    Wynn TA. 2008. Cellular and molecular mechanisms of fibrosis. J. Pathol. 214:199–210
    [Google Scholar]
  6. 6. 
    Forbes SJ, Newsome PN. 2016. Liver regeneration—mechanisms and models to clinical application. Nat. Rev. Gastroenterol. Hepatol. 13:473–85
    [Google Scholar]
  7. 7. 
    Michalopoulos GK, Khan Z. 2015. Liver stem cells: experimental findings and implications for human liver disease. Gastroenterology 149:876–82
    [Google Scholar]
  8. 8. 
    Fausto N, Campbell JS. 2003. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech. Dev. 120:117–30
    [Google Scholar]
  9. 9. 
    Tabibian JH, Masyuk AI, Masyuk TV, O'Hara SP, LaRusso NF 2013. Physiology of cholangiocytes. Compr. Physiol. 3:541–65
    [Google Scholar]
  10. 10. 
    Roskams TA, Theise ND, Balabaud C, Bhagat G, Bhathal PS et al. 2004. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology 39:1739–45
    [Google Scholar]
  11. 11. 
    Sato K, Marzioni M, Meng F, Francis H, Glaser S, Alpini G 2019. Ductular reaction in liver diseases: pathological mechanisms and translational significances. Hepatology 69:420–30
    [Google Scholar]
  12. 12. 
    Kim WR, Lake JR, Smith JM, Schladt DP, Skeans MA et al. 2018. OPTN/SRTR 2016 annual data report: liver. Am. J. Transplant. 18:Suppl. 1172–253
    [Google Scholar]
  13. 13. 
    Katoonizadeh A, Nevens F, Verslype C, Pirenne J, Roskams T 2006. Liver regeneration in acute severe liver impairment: a clinicopathological correlation study. Liver Int 26:1225–33
    [Google Scholar]
  14. 14. 
    Weng HL, Cai X, Yuan X, Liebe R, Dooley S, Li H, Wang TL 2015. Two sides of one coin: massive hepatic necrosis and progenitor cell–mediated regeneration in acute liver failure. Front. Physiol. 6:178
    [Google Scholar]
  15. 15. 
    Stueck AE, Wanless IR. 2015. Hepatocyte buds derived from progenitor cells repopulate regions of parenchymal extinction in human cirrhosis. Hepatology 61:1696–707
    [Google Scholar]
  16. 16. 
    Dechêne A, Sowa JP, Gieseler RK, Jochum C, Bechmann LP et al. 2010. Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation. Hepatology 52:1008–16
    [Google Scholar]
  17. 17. 
    Williams MJ, Clouston AD, Forbes SJ 2014. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology 146:349–56
    [Google Scholar]
  18. 18. 
    Lowes KN, Brennan BA, Yeoh GC, Olynyk JK 1999. Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am. J. Pathol. 154:537–41
    [Google Scholar]
  19. 19. 
    Gouw AS, Clouston AD, Theise ND 2011. Ductular reactions in human liver: diversity at the interface. Hepatology 54:1853–63
    [Google Scholar]
  20. 20. 
    Machado MV, Michelotti GA, Pereira TA, Xie G, Premont R et al. 2015. Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. J. Hepatol. 63:962–70
    [Google Scholar]
  21. 21. 
    Guldiken N, Kobazi Ensari G, Lahiri P, Couchy G, Preisinger C et al. 2016. Keratin 23 is a stress-inducible marker of mouse and human ductular reaction in liver disease. J. Hepatol. 65:552–59
    [Google Scholar]
  22. 22. 
    Helal TESA, Ehsan NA, Radwan NA, Abdelsameea E 2018. Relationship between hepatic progenitor cells and stellate cells in chronic hepatitis C genotype 4. APMIS 126:14–20
    [Google Scholar]
  23. 23. 
    El-Araby HA, Ehsan NA, Konsowa HA, Abd-Elaati BM, Sira AM 2015. Hepatic progenitor cells in children with chronic hepatitis C: correlation with histopathology, viremia, and treatment response. Eur. J. Gastroenterol. Hepatol. 27:561–69
    [Google Scholar]
  24. 24. 
    Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA et al. 2007. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction. Gastroenterology 133:80–90
    [Google Scholar]
  25. 25. 
    Gadd VL, Skoien R, Powell EE, Fagan KJ, Winterford C et al. 2014. The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease. Hepatology 59:1393–405
    [Google Scholar]
  26. 26. 
    Zhao L, Westerhoff M, Pai RK, Choi WT, Gao ZH, Hart J 2018. Centrilobular ductular reaction correlates with fibrosis stage and fibrosis progression in non-alcoholic steatohepatitis. Mod. Pathol. 31:150–59
    [Google Scholar]
  27. 27. 
    Carpino G, Nobili V, Renzi A, De Stefanis C, Stronati L et al. 2016. Macrophage activation in pediatric nonalcoholic fatty liver disease (NAFLD) correlates with hepatic progenitor cell response via Wnt3a pathway. PLOS ONE 11:e0157246
    [Google Scholar]
  28. 28. 
    Carpino G, Cardinale V, Folseraas T, Overi D, Floreani A et al. 2018. Hepatic stem/progenitor cell activation differs between primary sclerosing and primary biliary cholangitis. Am. J. Pathol. 188:627–39
    [Google Scholar]
  29. 29. 
    Govaere O, Cockell S, Van Haele M, Wouters J, Van Delm W et al. 2019. High-throughput sequencing identifies aetiology-dependent differences in ductular reaction in human chronic liver disease. J. Pathol. 248:66–76
    [Google Scholar]
  30. 30. 
    Svegliati-Baroni G, De Minicis S, Marzioni M 2008. Hepatic fibrogenesis in response to chronic liver injury: novel insights on the role of cell-to-cell interaction and transition. Liver Int 28:1052–64
    [Google Scholar]
  31. 31. 
    Aguilar-Bravo B, Rodrigo-Torres D, Ariño S, Coll M, Pose E et al. 2019. Ductular reaction cells display an inflammatory profile and recruit neutrophils in alcoholic hepatitis. Hepatology 69:2180–95
    [Google Scholar]
  32. 32. 
    Elßner C, Goeppert B, Longerich T, Scherr AL, Stindt J et al. 2019. Nuclear translocation of RELB is increased in diseased human liver and promotes ductular reaction and biliary fibrosis in mice. Gastroenterology 156:1190–205.e14
    [Google Scholar]
  33. 33. 
    Yu LX, Ling Y, Wang HY 2018. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis. Oncol 2:6
    [Google Scholar]
  34. 34. 
    Sia D, Villanueva A, Friedman SL, Llovet JM 2017. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152:745–61
    [Google Scholar]
  35. 35. 
    Roskams T. 2006. Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene 25:3818–22
    [Google Scholar]
  36. 36. 
    Ye F, Jing YY, Guo SW, Yu GF, Fan QM et al. 2014. Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection. Cell Biosci 4:50
    [Google Scholar]
  37. 37. 
    Xu M, Xie F, Qian G, Jing Y, Zhang S et al. 2014. Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma. BMC Cancer 14:65
    [Google Scholar]
  38. 38. 
    Cai X, Zhai J, Kaplan DE, Zhang Y, Zhou L et al. 2012. Background progenitor activation is associated with recurrence after hepatectomy of combined hepatocellular–cholangiocarcinoma. Hepatology 56:1804–16
    [Google Scholar]
  39. 39. 
    Gordillo M, Evans T, Gouon-Evans V 2015. Orchestrating liver development. Development 142:2094–108
    [Google Scholar]
  40. 40. 
    Gérard C, Tys J, Lemaigre FP 2017. Gene regulatory networks in differentiation and direct reprogramming of hepatic cells. Semin. Cell Dev. Biol. 66:43–50
    [Google Scholar]
  41. 41. 
    Suzuki A, Zheng YW, Kaneko S, Onodera M, Fukao K et al. 2002. Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J. Cell Biol. 156:173–84
    [Google Scholar]
  42. 42. 
    Tanimizu N, Nishikawa M, Saito H, Tsujimura T, Miyajima A 2003. Isolation of hepatoblasts based on the expression of Dlk/Pref-1. J. Cell Sci. 116:1775–86
    [Google Scholar]
  43. 43. 
    Nava S, Westgren M, Jaksch M, Tibell A, Broomé U et al. 2005. Characterization of cells in the developing human liver. Differentiation 73:249–60
    [Google Scholar]
  44. 44. 
    Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J et al. 2007. Human hepatic stem cells from fetal and postnatal donors. J. Exp. Med. 204:1973–87
    [Google Scholar]
  45. 45. 
    Dan YY, Riehle KJ, Lazaro C, Teoh N, Haque J et al. 2006. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. PNAS 103:9912–17
    [Google Scholar]
  46. 46. 
    Oertel M, Menthena A, Dabeva MD, Shafritz DA 2006. Cell competition leads to a high level of normal liver reconstitution by transplanted fetal liver stem/progenitor cells. Gastroenterology 130:507–20
    [Google Scholar]
  47. 47. 
    Turner R, Lozoya O, Wang Y, Cardinale V, Gaudio E et al. 2011. Human hepatic stem cell and maturational liver lineage biology. Hepatology 53:1035–45
    [Google Scholar]
  48. 48. 
    Cardinale V, Wang Y, Carpino G, Cui CB, Gatto M et al. 2011. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology 54:2159–72
    [Google Scholar]
  49. 49. 
    Isse K, Lesniak A, Grama K, Maier J, Specht S et al. 2013. Preexisting epithelial diversity in normal human livers: a tissue-tethered cytometric analysis in portal/periportal epithelial cells. Hepatology 57:1632–43
    [Google Scholar]
  50. 50. 
    Kamiya A, Kakinuma S, Yamazaki Y, Nakauchi H 2009. Enrichment and clonal culture of progenitor cells during mouse postnatal liver development in mice. Gastroenterology 137:1114–26.e14
    [Google Scholar]
  51. 51. 
    Okabe M, Tsukahara Y, Tanaka M, Suzuki K, Saito S et al. 2009. Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse liver. Development 136:1951–60
    [Google Scholar]
  52. 52. 
    Dorrell C, Erker L, Schug J, Kopp JL, Canaday PS et al. 2011. Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev 25:1193–203
    [Google Scholar]
  53. 53. 
    Tanimizu N, Kobayashi S, Ichinohe N, Mitaka T 2014. Downregulation of miR122 by grainyhead-like 2 restricts the hepatocytic differentiation potential of adult liver progenitor cells. Development 141:4448–56
    [Google Scholar]
  54. 54. 
    Tarlow BD, Finegold MJ, Grompe M 2014. Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 60:278–89
    [Google Scholar]
  55. 55. 
    Li B, Dorrell C, Canaday PS, Pelz C, Haft A et al. 2017. Adult mouse liver contains two distinct populations of cholangiocytes. Stem Cell Rep 9:478–89
    [Google Scholar]
  56. 56. 
    Kuwahara R, Kofman AV, Landis CS, Swenson ES, Barendswaard E, Theise ND 2008. The hepatic stem cell niche: identification by label-retaining cell assay. Hepatology 47:1994–2002
    [Google Scholar]
  57. 57. 
    Kordes C, Häussinger D. 2013. Hepatic stem cell niches. J. Clin. Investig. 123:1874–80
    [Google Scholar]
  58. 58. 
    Sicklick JK, Li YX, Melhem A, Schmelzer E, Zdanowicz M et al. 2006. Hedgehog signaling maintains resident hepatic progenitors throughout life. Am. J. Physiol. Gastrointest. Liver Physiol. 290:G859–70
    [Google Scholar]
  59. 59. 
    Español-Suñer R, Carpentier R, Van Hul N, Legry V, Achouri Y et al. 2012. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143:1564–75.e7
    [Google Scholar]
  60. 60. 
    Clayton E, Forbes SJ. 2009. The isolation and in vitro expansion of hepatic Sca-1 progenitor cells. Biochem. Biophys. Res. Commun. 381:549–53
    [Google Scholar]
  61. 61. 
    Lorenzini S, Bird TG, Boulter L, Bellamy C, Samuel K et al. 2010. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver. Gut 59:645–54
    [Google Scholar]
  62. 62. 
    Van Hul NK, Abarca-Quinones J, Sempoux C, Horsmans Y, Leclercq IA 2009. Relation between liver progenitor cell expansion and extracellular matrix deposition in a CDE-induced murine model of chronic liver injury. Hepatology 49:1625–35
    [Google Scholar]
  63. 63. 
    Factor VM, Radaeva SA, Thorgeirsson SS 1994. Origin and fate of oval cells in Dipin-induced hepatocarcinogenesis in the mouse. Am. J. Pathol. 145:409–22
    [Google Scholar]
  64. 64. 
    Farber E. 1956. 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 16:142–48
    [Google Scholar]
  65. 65. 
    Dempo K, Chisaka N, Yoshida Y, Kaneko A, Onoé T 1975. Immunofluorescent study on α-fetoprotein-producing cells in the early stage of 3′-methyl-4-dimethylaminoazobenzene carcinogenesis. Cancer Res 35:1282–87
    [Google Scholar]
  66. 66. 
    Inaoka Y. 1967. Significance of the so-called oval cell proliferation during azo-dye hepatocarcinogenesis. Gan 58:355–66
    [Google Scholar]
  67. 67. 
    Ogawa K, Minase T, Onhoe T 1974. Demonstration of glucose 6-phosphatase activity in the oval cells of rat liver and the significance of the oval cells in azo dye carcinogenesis. Cancer Res 34:3379–86
    [Google Scholar]
  68. 68. 
    Tag CG, Sauer-Lehnen S, Weiskirchen S, Borkham-Kamphorst E, Tolba RH et al. 2015. Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis. J. Vis. Exp. 10:e52438
    [Google Scholar]
  69. 69. 
    Rubin E. 1964. The origin and fate of proliferated bile ductular cells. Exp. Mol. Pathol. 3:279–86
    [Google Scholar]
  70. 70. 
    Grisham JW, Porta EA. 1964. Origin and fate of proliferated hepatic ductal cells in the rat: electron microscopic and autoradiographic studies. Exp. Mol. Pathol. 3:242–61
    [Google Scholar]
  71. 71. 
    Tatematsu M, Ho RH, Kaku T, Ekem JK, Farber E 1984. Studies on the proliferation and fate of oval cells in the liver of rats treated with 2-acetylaminofluorene and partial hepatectomy. Am. J. Pathol. 114:418–30
    [Google Scholar]
  72. 72. 
    Solt D, Farber E. 1976. New principle for the analysis of chemical carcinogenesis. Nature 263:701–3
    [Google Scholar]
  73. 73. 
    Petersen BE, Zajac VF, Michalopoulos GK 1997. Bile ductular damage induced by methylene dianiline inhibits oval cell activation. Am. J. Pathol. 151:905–9
    [Google Scholar]
  74. 74. 
    Evarts RP, Nagy P, Marsden E, Thorgeirsson SS 1987. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis 8:1737–40
    [Google Scholar]
  75. 75. 
    Evarts RP, Nagy P, Nakatsukasa H, Marsden E, Thorgeirsson SS 1989. In vivo differentiation of rat liver oval cells into hepatocytes. Cancer Res 49:1541–47
    [Google Scholar]
  76. 76. 
    Alison M, Golding M, Lalani EN, Nagy P, Thorgeirsson S, Sarraf C 1997. Wholesale hepatocytic differentiation in the rat from ductular oval cells, the progeny of biliary stem cells. J. Hepatol. 26:343–52
    [Google Scholar]
  77. 77. 
    Copeland DH, Salmon WD. 1946. The occurrence of neoplasms in the liver, lungs, and other tissues of rats as a result of prolonged choline deficiency. Am. J. Pathol. 22:1059–79
    [Google Scholar]
  78. 78. 
    Newberne PM, Camargo JL, Clark AJ 1982. Choline deficiency, partial hepatectomy, and liver tumors in rats and mice. Toxicol. Pathol. 10:95–106
    [Google Scholar]
  79. 79. 
    Alix JH. 1982. Molecular aspects of the in vivo and in vitro effects of ethionine, an analog of methionine. Microbiol. Rev. 46:281–95
    [Google Scholar]
  80. 80. 
    Shinozuka H, Lombardi B, Sell S, Iammarino RM 1978. Early histological and functional alterations of ethionine liver carcinogenesis in rats fed a choline-deficient diet. Cancer Res 38:1092–98
    [Google Scholar]
  81. 81. 
    Akhurst B, Croager EJ, Farley-Roche CA, Ong JK, Dumble ML et al. 2001. A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver. Hepatology 34:519–22
    [Google Scholar]
  82. 82. 
    Pradhan-Sundd T, Vats R, Russell JM, Singh S, Michael AA et al. 2018. Dysregulated bile transporters and impaired tight junctions during chronic liver injury in mice. Gastroenterology 155:1218–32
    [Google Scholar]
  83. 83. 
    Knight B, Matthews VB, Akhurst B, Croager EJ, Klinken E et al. 2005. Liver inflammation and cytokine production, but not acute phase protein synthesis, accompany the adult liver progenitor (oval) cell response to chronic liver injury. Immunol. Cell Biol. 83:364–74
    [Google Scholar]
  84. 84. 
    Knight B, Akhurst B, Matthews VB, Ruddell RG, Ramm GA et al. 2007. Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice. J. Hepatol. 46:134–41
    [Google Scholar]
  85. 85. 
    Strick-Marchand H, Masse GX, Weiss MC, Di Santo JP 2008. Lymphocytes support oval cell–dependent liver regeneration. J. Immunol. 181:2764–71
    [Google Scholar]
  86. 86. 
    Bird TG, Lu WY, Boulter L, Gordon-Keylock S, Ridgway RA et al. 2013. Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling. PNAS 110:6542–47
    [Google Scholar]
  87. 87. 
    Carpentier R, Suñer RE, van Hul N, Kopp JL, Beaudry JB et al. 2011. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 141:1432–38.e4
    [Google Scholar]
  88. 88. 
    Shin S, Upadhyay N, Greenbaum LE, Kaestner KH 2015. Ablation of Foxl1-Cre–labeled hepatic progenitor cells and their descendants impairs recovery of mice from liver injury. Gastroenterology 148:192–202.e3
    [Google Scholar]
  89. 89. 
    Rodrigo-Torres D, Affò S, Coll M, Morales-Ibanez O, Millán C et al. 2014. The biliary epithelium gives rise to liver progenitor cells. Hepatology 60:1367–77
    [Google Scholar]
  90. 90. 
    Yanger K, Knigin D, Zong Y, Maggs L, Gu G et al. 2014. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 15:340–49
    [Google Scholar]
  91. 91. 
    Raven A, Lu WY, Man TY, Ferreira-Gonzalez S, O'Duibhir E et al. 2017. Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature 547:350–54
    [Google Scholar]
  92. 92. 
    Russell JO, Lu WY, Okabe H, Abrams M, Oertel M et al. 2019. Hepatocyte-specific β-catenin deletion during severe liver injury provokes cholangiocytes to differentiate into hepatocytes. Hepatology 69:742–59
    [Google Scholar]
  93. 93. 
    Malato Y, Naqvi S, Schürmann N, Ng R, Wang B et al. 2011. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J. Clin. Investig. 121:4850–60
    [Google Scholar]
  94. 94. 
    Schaub JR, Malato Y, Gormond C, Willenbring H 2014. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep 8:933–39
    [Google Scholar]
  95. 95. 
    Lu WY, Bird TG, Boulter L, Tsuchiya A, Cole AM et al. 2015. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat. Cell Biol. 17:971–83
    [Google Scholar]
  96. 96. 
    Fickert P, Stöger U, Fuchsbichler A, Moustafa T, Marschall HU et al. 2007. A new xenobiotic-induced mouse model of sclerosing cholangitis and biliary fibrosis. Am. J. Pathol. 171:525–36
    [Google Scholar]
  97. 97. 
    Yanger K, Zong Y, Maggs LR, Shapira SN, Maddipati R et al. 2013. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev 27:719–24
    [Google Scholar]
  98. 98. 
    Huch M, Dorrell C, Boj SF, van Es JH, Li VS et al. 2013. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494:247–50
    [Google Scholar]
  99. 99. 
    Deng X, Zhang X, Li W, Feng RX, Li L et al. 2018. Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 23:114–22.e3
    [Google Scholar]
  100. 100. 
    Aoki R, Chiba T, Miyagi S, Negishi M, Konuma T et al. 2010. The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells. J. Hepatol. 52:854–63
    [Google Scholar]
  101. 101. 
    Koike H, Ouchi R, Ueno Y, Nakata S, Obana Y et al. 2014. Polycomb group protein Ezh2 regulates hepatic progenitor cell proliferation and differentiation in murine embryonic liver. PLOS ONE 9:e104776
    [Google Scholar]
  102. 102. 
    Jalan-Sakrikar N, De Assuncao TM, Lu J, Almada LL, Lomberk G et al. 2016. Hedgehog signaling overcomes an EZH2-dependent epigenetic barrier to promote cholangiocyte expansion. PLOS ONE 11:e0168266
    [Google Scholar]
  103. 103. 
    Ko S, Choi TY, Russell JO, So J, Monga SPS, Shin D 2016. Bromodomain and extraterminal (BET) proteins regulate biliary-driven liver regeneration. J. Hepatol. 64:316–25
    [Google Scholar]
  104. 104. 
    Hunter AL, Holscher MA, Neal RA 1977. Thioacetamide-induced hepatic necrosis. I. Involvement of the mixed-function oxidase enzyme system. J. Pharmacol. Exp. Ther. 200:439–48
    [Google Scholar]
  105. 105. 
    Müller A, Machnik F, Zimmermann T, Schubert H 1988. Thioacetamide-induced cirrhosis-like liver lesions in rats—usefulness and reliability of this animal model. Exp. Pathol. 34:229–36
    [Google Scholar]
  106. 106. 
    Gracz AD, Fuller MK, Wang F, Li L, Stelzner M et al. 2013. CD24 and CD44 mark human intestinal epithelial cell populations with characteristics of active and facultative stem cells. Stem Cells 31:2024–30
    [Google Scholar]
  107. 107. 
    Michalopoulos GK, Bowen WC, Mulè K, Lopez-Talavera JC, Mars W 2002. Hepatocytes undergo phenotypic transformation to biliary epithelium in organoid cultures. Hepatology 36:278–83
    [Google Scholar]
  108. 108. 
    Michalopoulos GK, Barua L, Bowen WC 2005. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 41:535–44
    [Google Scholar]
  109. 109. 
    Yovchev MI, Locker J, Oertel M 2016. Biliary fibrosis drives liver repopulation and phenotype transition of transplanted hepatocytes. J. Hepatol. 64:1348–57
    [Google Scholar]
  110. 110. 
    Tanimizu N, Nishikawa Y, Ichinohe N, Akiyama H, Mitaka T 2014. Sry HMG box protein 9-positive (Sox9+) epithelial cell adhesion molecule-negative (EpCAM) biphenotypic cells derived from hepatocytes are involved in mouse liver regeneration. J. Biol. Chem. 289:7589–98
    [Google Scholar]
  111. 111. 
    Nagahama Y, Sone M, Chen X, Okada Y, Yamamoto M et al. 2014. Contributions of hepatocytes and bile ductular cells in ductular reactions and remodeling of the biliary system after chronic liver injury. Am. J. Pathol. 184:3001–12
    [Google Scholar]
  112. 112. 
    Lin S, Nascimento EM, Gajera CR, Chen L, Neuhöfer P et al. 2018. Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature 556:244–48
    [Google Scholar]
  113. 113. 
    Sekiya S, Suzuki A. 2014. Hepatocytes, rather than cholangiocytes, can be the major source of primitive ductules in the chronically injured mouse liver. Am. J. Pathol. 184:1468–78
    [Google Scholar]
  114. 114. 
    Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P et al. 2012. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat. Med. 18:572–79
    [Google Scholar]
  115. 115. 
    Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B et al. 2014. Hippo pathway activity influences liver cell fate. Cell 157:1324–38
    [Google Scholar]
  116. 116. 
    Font-Burgada J, Shalapour S, Ramaswamy S, Hsueh B, Rossell D et al. 2015. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162:766–79
    [Google Scholar]
  117. 117. 
    Thompson MD, Awuah P, Singh S, Monga SP 2010. Disparate cellular basis of improved liver repair in β-catenin-overexpressing mice after long-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Am. J. Pathol. 2010 177:1812–22
    [Google Scholar]
  118. 118. 
    Okabe H, Yang J, Sylakowski K, Yovchev M, Miyagawa Y et al. 2016. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology 64:1652–66
    [Google Scholar]
  119. 119. 
    Tarlow BD, Pelz C, Naugler WE, Wakefield L, Wilson EM et al. 2014. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15:605–18
    [Google Scholar]
  120. 120. 
    Schaub JR, Huppert KA, Kurial SNT, Hsu BY, Cast AE et al. 2018. De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. Nature 557:247–51
    [Google Scholar]
  121. 121. 
    Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H et al. 2006. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell–like properties. Hepatology 44:240–51
    [Google Scholar]
  122. 122. 
    Ma S, Chan KW, Hu L, Lee TK, Wo JY et al. 2007. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 132:2542–56
    [Google Scholar]
  123. 123. 
    Marquardt JU, Raggi C, Andersen JB, Seo D, Avital I et al. 2011. Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Hepatology 54:1031–42
    [Google Scholar]
  124. 124. 
    Braun L, Goyette M, Yaswen P, Thompson NL, Fausto N 1987. Growth in culture and tumorigenicity after transfection with the ras oncogene of liver epithelial cells from carcinogen-treated rats. Cancer Res 47:4116–24
    [Google Scholar]
  125. 125. 
    Yamashita T, Ji J, Budhu A, Forgues M, Yang W et al. 2009. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 136:1012–24
    [Google Scholar]
  126. 126. 
    Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P et al. 2006. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat. Med. 12:410–16
    [Google Scholar]
  127. 127. 
    Chiba T, Zheng YW, Kita K, Yokosuka O, Saisho H et al. 2007. Enhanced self-renewal capability in hepatic stem/progenitor cells drives cancer initiation. Gastroenterology 133:937–50
    [Google Scholar]
  128. 128. 
    Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN et al. 2014. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature 513:110–14
    [Google Scholar]
  129. 129. 
    Tang Y, Kitisin K, Jogunoori W, Li C, Deng CX et al. 2008. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling. PNAS 105:2445–50
    [Google Scholar]
  130. 130. 
    He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H et al. 2013. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155:384–96
    [Google Scholar]
  131. 131. 
    Tummala KS, Brandt M, Teijeiro A, Graña O, Schwabe RF et al. 2017. Hepatocellular carcinomas originate predominantly from hepatocytes and benign lesions from hepatic progenitor cells. Cell Rep 19:584–600
    [Google Scholar]
  132. 132. 
    Mu X, Español-Suñer R, Mederacke I, Affò S, Manco R et al. 2015. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment. J. Clin. Investig. 125:3891–903
    [Google Scholar]
  133. 133. 
    Holczbauer Á, Factor VM, Andersen JB, Marquardt JU, Kleiner DE et al. 2013. Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology 145:221–31
    [Google Scholar]
  134. 134. 
    Benhamouche S, Curto M, Saotome I, Gladden AB, Liu CH et al. 2010. Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver. Genes Dev 24:1718–30
    [Google Scholar]
  135. 135. 
    Fitamant J, Kottakis F, Benhamouche S, Tian HS, Chuvin N et al. 2015. YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression. Cell Rep 17:1692–707
    [Google Scholar]
  136. 136. 
    Sekiya S, Suzuki A. 2012. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J. Clin. Investig. 122:3914–18
    [Google Scholar]
  137. 137. 
    Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N et al. 2012. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Investig. 122:2911–15
    [Google Scholar]
  138. 138. 
    Ikenoue T, Terakado Y, Nakagawa H, Hikiba Y, Fujii T et al. 2016. A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion. Sci. Rep. 6:23899
    [Google Scholar]
  139. 139. 
    Dill MT, Tornillo L, Fritzius T, Terracciano L, Semela D et al. 2013. Constitutive Notch2 signaling induces hepatic tumors in mice. Hepatology 57:1607–19
    [Google Scholar]
  140. 140. 
    Terada M, Horisawa K, Miura S, Takashima Y, Ohkawa Y et al. 2016. Kupffer cells induce Notch-mediated hepatocyte conversion in a common mouse model of intrahepatic cholangiocarcinoma. Sci. Rep. 6:34691
    [Google Scholar]
  141. 141. 
    Choi TY, Ninov N, Stainier DY, Shin D 2014. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 146:776–88
    [Google Scholar]
  142. 142. 
    He J, Lu H, Zou Q, Luo L 2014. Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 146:789–800.e8
    [Google Scholar]
  143. 143. 
    Huang M, Chang A, Choi M, Zhou D, Anania FA, Shin CH 2014. Antagonistic interaction between Wnt and Notch activity modulates the regenerative capacity of a zebrafish fibrotic liver model. Hepatology 60:1753–66
    [Google Scholar]
  144. 144. 
    Ninov N, Hesselson D, Gut P, Zhou A, Fidelin K, Stainier DY 2013. Metabolic regulation of cellular plasticity in the pancreas. Curr. Biol. 23:1242–50
    [Google Scholar]
  145. 145. 
    Ko S, Russell JO, Tian J, Gao C, Kobayashi M et al. 2019. Hdac1 regulates differentiation of bipotent liver progenitor cells during regeneration via Sox9b and Cdk8. Gastroenterology 156:187–202.e14
    [Google Scholar]
  146. 146. 
    Zhang X, Du G, Xu Y, Li X, Fan W et al. 2016. Inhibition of Notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes. Lab Investig 96:350–60
    [Google Scholar]
  147. 147. 
    Yongping M, Zhang X, Xuewei L, Fan W, Chen J et al. 2015. Astragaloside prevents BDL-induced liver fibrosis through inhibition of Notch signaling activation. J. Ethnopharmacol. 169:200–9
    [Google Scholar]
  148. 148. 
    Fiorotto R, Raizner A, Morell CM, Torsello B, Scirpo R et al. 2013. Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. J. Hepatol. 59:124–30
    [Google Scholar]
  149. 149. 
    Paganelli M, Nyabi O, Sid B, Evraerts J, El Malmi I et al. 2014. Downregulation of Sox9 expression associates with hepatogenic differentiation of human liver mesenchymal stem/progenitor cells. Stem Cells Dev 23:1377–91
    [Google Scholar]
  150. 150. 
    Choi TY, Khaliq M, Tsurusaki S, Ninov N, Stainier DYR et al. 2017. Bone morphogenetic protein signaling governs biliary-driven liver regeneration in zebrafish through tbx2b and id2a. Hepatology 66:1616–30
    [Google Scholar]
  151. 151. 
    Hardman RC, Volz DC, Kullman SW, Hinton DE 2007. An in vivo look at vertebrate liver architecture: three-dimensional reconstructions from medaka (Oryzias latipes). Anat. Rec. 290:770–82
    [Google Scholar]
  152. 152. 
    Lorent K, Moore JC, Siekmann AF, Lawson N, Pack M 2010. Reiterative use of the Notch signal during zebrafish intrahepatic biliary development. Dev. Dyn. 239:855–64
    [Google Scholar]
  153. 153. 
    Goessling W, Sadler KC. 2015. Zebrafish: an important tool for liver disease research. Gastroenterology 149:1361–77
    [Google Scholar]
  154. 154. 
    Russell JO, Monga SP. 2018. Wnt/β-catenin signaling in liver development, homeostasis, and pathobiology. Annu. Rev. Pathol. Mech. Dis. 13:351–78
    [Google Scholar]
  155. 155. 
    Soto-Gutierrez A, Gough A, Vernetti LA, Taylor DL, Monga SP 2017. Pre-clinical and clinical investigations of metabolic zonation in liver diseases: the potential of microphysiology systems. Exp. Biol. Med. 242:1605–16
    [Google Scholar]
  156. 156. 
    Ko S, Monga SP. 2018. Hepatic zonation now on hormones!. Hepatology 69:1339–42
    [Google Scholar]
  157. 157. 
    Chu J, Sadler KC. 2009. New school in liver development: lessons from zebrafish. Hepatology 50:1656–63
    [Google Scholar]
  158. 158. 
    Kulkeaw K, Sugiyama D. 2012. Zebrafish erythropoiesis and the utility of fish as models of anemia. Stem Cell Res. Ther. 3:55
    [Google Scholar]
  159. 159. 
    Langenau DM, Zon LI. 2005. The zebrafish: a new model of T-cell and thymic development. Nat. Rev. Immunol. 5:307–17
    [Google Scholar]
  160. 160. 
    Iismaa SE, Kaidonis X, Nicks AM, Bogush N, Kikuchi K et al. 2018. Comparative regenerative mechanisms across different mammalian tissues. NPJ Regen. Med. 3:6
    [Google Scholar]
  161. 161. 
    Hernandez-Martinez JM, Forrest CM, Darlington LG, Smith RA, Stone TW 2017. Quinolinic acid induces neuritogenesis in SH-SY5Y neuroblastoma cells independently of NMDA receptor activation. Eur. J. Neurosci. 45:700–11
    [Google Scholar]
  162. 162. 
    Robinson MA, Graham DJ, Morrish F, Hockenbery D, Gamble LJ 2015. Lipid analysis of eight human breast cancer cell lines with ToF-SIMS. Biointerphases 11:02A303
    [Google Scholar]
  163. 163. 
    Lin Y, Fang ZP, Liu HJ, Wang LJ, Cheng Z et al. 2017. HGF/R-spondin1 rescues liver dysfunction through the induction of Lgr5. Nat. Commun. 8:1175
    [Google Scholar]
  164. 164. 
    Xu J, Tan Y, Shao X, Zhang C, He Y, Wang J, Xi Y 2018. Evaluation of NCAM and c-Kit as hepatic progenitor cell markers for intrahepatic cholangiocarcinomas. Pathol. Res. Pract. 214:2011–17
    [Google Scholar]
/content/journals/10.1146/annurev-pathmechdis-012419-032824
Loading
/content/journals/10.1146/annurev-pathmechdis-012419-032824
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error