The mammalian liver is one of the most regenerative tissues in the body, capable of fully recovering mass and function after a variety of injuries. This factor alone makes the liver unusual among mammalian tissues, but even more atypical is the widely held notion that the method of repair depends on the manner of injury. Specifically, the liver is believed to regenerate via replication of existing cells under certain conditions and via differentiation from specialized cells—so-called facultative stem cells—under others. Nevertheless, despite the liver's dramatic and unique regenerative response, the cellular and molecular features of liver homeostasis and regeneration are only now starting to come into relief. This review provides an overview of normal liver function and development and focuses on the evidence for and against various models of liver homeostasis and regeneration.


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Literature Cited

  1. Slack JM. 1.  2008. Origin of stem cells in organogenesis. Science 322:1498–501 [Google Scholar]
  2. Weissman IL. 2.  2000. Stem cells: units of development, units of regeneration, and units in evolution. Cell 100:157–68 [Google Scholar]
  3. Simon A, Tanaka EM. 3.  2013. Limb regeneration. Wiley Interdiscip. Rev. Dev. Biol. 2:291–300 [Google Scholar]
  4. Tornini VA, Poss KD. 4.  2014. Keeping at arm's length during regeneration. Dev. Cell 29:139–45 [Google Scholar]
  5. Thorel F, Nepote V, Avril I, Kohno K, Desgraz R. 5.  et al. 2010. Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss. Nature 464:1149–54 [Google Scholar]
  6. Yanger K, Zong Y, Maggs LR, Shapira SN, Maddipati R. 6.  et al. 2013. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 27:719–24 [Google Scholar]
  7. Tata PR, Mou H, Pardo-Saganta A, Zhao R, Prabhu M. 7.  et al. 2013. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 503:218–23 [Google Scholar]
  8. Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X. 8.  et al. 2013. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4:2823 [Google Scholar]
  9. Wells RG. 9.  2014. The portal fibroblast: not just a poor man's stellate cell. Gastroenterology 147:41–47 [Google Scholar]
  10. Scholten D, Osterreicher CH, Scholten A, Iwaisako K, Gu G. 10.  et al. 2010. Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 139:987–98 [Google Scholar]
  11. Chu AS, Diaz R, Hui JJ, Yanger K, Zong Y. 11.  et al. 2011. Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis. Hepatology 53:1685–95 [Google Scholar]
  12. Yang J, Mowry LE, Nejak-Bowen KN, Okabe H, Diegel CR. 12.  et al. 2014. Beta-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation!. Hepatology 60:3964–76 [Google Scholar]
  13. Celton-Morizur S, Desdouets C. 13.  2010. Polyploidization of liver cells. Adv. Exp. Med. Biol. 676:123–35 [Google Scholar]
  14. Celton-Morizur S, Merlen G, Couton D, Margall-Ducos G, Desdouets C. 14.  2009. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J. Clin. Investig. 119:1880–87 [Google Scholar]
  15. Duncan AW, Hanlon Newell AE, Bi W, Finegold MJ, Olson SB. 15.  et al. 2012. Aneuploidy as a mechanism for stress-induced liver adaptation. J. Clin. Investig. 122:3307–15 [Google Scholar]
  16. Zorn AM. 16.  2008. Liver development. StemBook The Stem Cell Research Community; doi: 10.3824/stembook.1.25.1. http://www.stembook.org/node/512 [Google Scholar]
  17. Si-Tayeb K, Lemaigre FP, Duncan SA. 17.  2010. Organogenesis and development of the liver. Dev. Cell 18:175–89 [Google Scholar]
  18. Le Douarin N. 18.  1968. Synthesis of glycogen in hepatocytes undergoing differentiation: role of homologous and heterologous mesenchyma. Dev. Biol. 17:101–14 [Google Scholar]
  19. Zaret KS, Grompe M. 19.  2008. Generation and regeneration of cells of the liver and pancreas. Science 322:1490–94 [Google Scholar]
  20. Lee CS, Friedman JR, Fulmer JT, Kaestner KH. 20.  2005. The initiation of liver development is dependent on Foxa transcription factors. Nature 435:944–47 [Google Scholar]
  21. Gouon-Evans V, Boussemart L, Gadue P, Nierhoff D, Koehler CI. 21.  et al. 2006. BMP-4 is required for hepatic specification of mouse embryonic stem cell–derived definitive endoderm. Nat. Biotechnol. 24:1402–11 [Google Scholar]
  22. Li L, Krantz ID, Deng Y, Genin A, Banta AB. 22.  et al. 1997. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat. Genet. 16:243–51 [Google Scholar]
  23. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID. 23.  et al. 1997. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat. Genet. 16:235–42 [Google Scholar]
  24. Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML. 24.  2010. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 137:4061–72 [Google Scholar]
  25. Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U. 25.  et al. 2008. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology 48:607–16 [Google Scholar]
  26. Kodama Y, Hijikata M, Kageyama R, Shimotohno K, Chiba T. 26.  2004. The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology 127:1775–86 [Google Scholar]
  27. Antoniou A, Raynaud P, Cordi S, Zong Y, Tronche F. 27.  et al. 2009. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 136:2325–33 [Google Scholar]
  28. Zong Y, Panikkar A, Xu J, Antoniou A, Raynaud P. 28.  et al. 2009. Notch signaling controls liver development by regulating biliary differentiation. Development 136:1727–39 [Google Scholar]
  29. Clotman F, Jacquemin P, Plumb-Rudewiez N, Pierreux CE, Van der Smissen P. 29.  et al. 2005. Control of liver cell fate decision by a gradient of TGFβ signaling modulated by Onecut transcription factors. Genes Dev. 19:1849–54 [Google Scholar]
  30. Zhang N, Bai H, David KK, Dong J, Zheng Y. 30.  et al. 2010. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19:27–38 [Google Scholar]
  31. Tan X, Yuan Y, Zeng G, Apte U, Thompson MD. 31.  et al. 2008. β-Catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development. Hepatology 47:1667–79 [Google Scholar]
  32. Decaens T, Godard C, de Reynies A, Rickman DS, Tronche F. 32.  et al. 2008. Stabilization of β-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology 47:247–58 [Google Scholar]
  33. Spence JR, Lange AW, Lin SC, Kaestner KH, Lowy AM. 33.  et al. 2009. Sox17 regulates organ lineage segregation of ventral foregut progenitor cells. Dev. Cell 17:62–74 [Google Scholar]
  34. Li J, Ning G, Duncan SA. 34.  2000. Mammalian hepatocyte differentiation requires the transcription factor HNF-4α. Genes Dev. 14:464–74 [Google Scholar]
  35. Odom DT, Dowell RD, Jacobsen ES, Nekludova L, Rolfe PA. 35.  et al. 2006. Core transcriptional regulatory circuitry in human hepatocytes. Mol. Syst. Biol. 2:2006.0017 [Google Scholar]
  36. Kyrmizi I, Hatzis P, Katrakili N, Tronche F, Gonzalez FJ, Talianidis I. 36.  2006. Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev. 20:2293–305 [Google Scholar]
  37. Laudadio I, Manfroid I, Achouri Y, Schmidt D, Wilson MD. 37.  et al. 2012. A feedback loop between the liver-enriched transcription factor network and miR-122 controls hepatocyte differentiation. Gastroenterology 142:119–29 [Google Scholar]
  38. Cai J, DeLaForest A, Fisher J, Urick A, Wagner T. 38.  et al. 2008. Protocol for directed differentiation of human pluripotent stem cells toward a hepatocyte fate. StemBook The Stem Cell Research Community; doi: 10.3824/stembook.1.52.1. http://www.stembook.org/node/721 [Google Scholar]
  39. Ogawa S, Surapisitchat J, Virtanen C, Ogawa M, Niapour M. 39.  et al. 2013. Three-dimensional culture and cAMP signaling promote the maturation of human pluripotent stem cell–derived hepatocytes. Development 140:3285–96 [Google Scholar]
  40. Shan J, Schwartz RE, Ross NT, Logan DJ, Thomas D. 40.  et al. 2013. Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat. Chem. Biol. 9:514–20 [Google Scholar]
  41. MacDonald RA. 41.  1961. “Lifespan” of liver cells. Autoradio-graphic study using tritiated thymidine in normal, cirrhotic, and partially hepatectomized rats. Arch. Intern. Med. 107:335–43 [Google Scholar]
  42. Sawada N, Ishikawa T. 42.  1988. Reduction of potential for replicative but not unscheduled DNA synthesis in hepatocytes isolated from aged as compared to young rats. Cancer Res. 48:1618–22 [Google Scholar]
  43. Zajicek G, Oren R, Weinreb M Jr. 43.  1985. The streaming liver. Liver 5:293–300 [Google Scholar]
  44. Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S. 44.  et al. 2011. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat. Genet. 43:34–41 [Google Scholar]
  45. Bralet MP, Branchereau S, Brechot C, Ferry N. 45.  1994. Cell lineage study in the liver using retroviral mediated gene transfer. Evidence against the streaming of hepatocytes in normal liver. Am. J. Pathol. 144:896–905 [Google Scholar]
  46. Magami Y, Azuma T, Inokuchi H, Kokuno S, Moriyasu F. 46.  et al. 2002. Cell proliferation and renewal of normal hepatocytes and bile duct cells in adult mouse liver. Liver 22:419–25 [Google Scholar]
  47. Malato Y, Naqvi S, Schürmann N, Ng R, Wang B. 47.  et al. 2011. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J. Clin. Investig. 121:1850–60 [Google Scholar]
  48. Español-Suñer R, Carpentier R, Van Hul N, Legry V, Achouri Y. 48.  et al. 2012. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143:1564–75.e7 [Google Scholar]
  49. Yanger K, Stanger BZ. 49.  2014. Liver cell reprogramming: parallels with iPSC biology. Cell Cycle 13:1211–12 [Google Scholar]
  50. Higgins GM, Anderson RM. 50.  1931. Experimental pathology of the liver. I. Restoration of the liver of the white rat following partial surgical removal. Arch. Pathol. 12:186–202 [Google Scholar]
  51. Miyaoka Y, Ebato K, Kato H, Arakawa S, Shimizu S, Miyajima A. 51.  2012. Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr. Biol. 22:1166–75 [Google Scholar]
  52. Michalopoulos GK. 52.  2007. Liver regeneration. J. Cell. Physiol. 213:286–300 [Google Scholar]
  53. Georgiev P, Jochum W, Heinrich S, Jang JH, Nocito A. 53.  et al. 2008. Characterization of time-related changes after experimental bile duct ligation. Br. J. Surg. 95:646–56 [Google Scholar]
  54. Chang ML, Yeh CT, Chang PY, Chen JC. 54.  2005. Comparison of murine cirrhosis models induced by hepatotoxin administration and common bile duct ligation. World J. Gastroenterol. 11:4167–72 [Google Scholar]
  55. Farber E. 55.  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]
  56. Popper H, Kent G, Stein R. 56.  1957. Ductular cell reaction in the liver in hepatic injury. J. Mt. Sinai Hosp. N. Y. 24:551–56 [Google Scholar]
  57. Leduc EH, Wilson JW. 57.  1958. Injury to liver cells in carbon tetrachloride poisoning; histochemical changes induced by carbon tetrachloride in mouse liver protected by sulfaguanidine. AMA Arch. Pathol. 65:147–57 [Google Scholar]
  58. Preisegger KH, Factor VM, Fuchsbichler A, Stumptner C, Denk H, Thorgeirsson SS. 58.  1999. Atypical ductular proliferation and its inhibition by transforming growth factor β1 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model for chronic alcoholic liver disease. Lab. Investig. 79:103–9 [Google Scholar]
  59. Akhurst B, Croager EJ, Farley-Roche CA, Ong JK, Dumble ML. 59.  et al. 2001. A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver. Hepatology 34:519–22 [Google Scholar]
  60. Wilson JW, Leduc EH. 60.  1958. Role of cholangioles in restoration of the liver of the mouse after dietary injury. J. Pathol. Bacteriol. 76:441–49 [Google Scholar]
  61. Zipori D. 61.  2004. The nature of stem cells: state rather than entity. Nat. Rev. Genet. 5:873–78 [Google Scholar]
  62. Roskams TA, Libbrecht L, Desmet VJ. 62.  2003. Progenitor cells in diseased human liver. Semin. Liver Dis. 23:385–96 [Google Scholar]
  63. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P. 63.  et al. 2006. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat. Med. 12:410–16 [Google Scholar]
  64. Grisham JW, Porta EA. 64.  1964. Origin and fate of proliferated hepatic ductal cells in the rat: electron microscopic and autoradiographic studies. Exp. Mol. Pathol. 86:242–61 [Google Scholar]
  65. Evarts RP, Nagy P, Nakatsukasa H, Marsden E, Thorgeirsson SS. 65.  1989. In vivo differentiation of rat liver oval cells into hepatocytes. Cancer Res. 49:1541–47 [Google Scholar]
  66. Gerber MA, Thung SN, Shen S, Stromeyer FW, Ishak KG. 66.  1983. Phenotypic characterization of hepatic proliferation. Antigenic expression by proliferating epithelial cells in fetal liver, massive hepatic necrosis, and nodular transformation of the liver. Am. J. Pathol. 110:70–74 [Google Scholar]
  67. Factor VM, Radaeva SA, Thorgeirsson SS. 67.  1994. Origin and fate of oval cells in dipin-induced hepatocarcinogenesis in the mouse. Am. J. Pathol. 145:409–22 [Google Scholar]
  68. Zhou H, Rogler LE, Teperman L, Morgan G, Rogler CE. 68.  2007. Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver. Hepatology 45:716–24 [Google Scholar]
  69. Paku S, Schnur J, Nagy P, Thorgeirsson SS. 69.  2001. Origin and structural evolution of the early proliferating oval cells in rat liver. Am. J. Pathol. 158:1313–23 [Google Scholar]
  70. Fausto N, Campbell JS. 70.  2003. The role of hepatocytes and oval cells in liver regeneration and repopulation. Mech. Dev. 120:117–30 [Google Scholar]
  71. Dorrell C, Grompe M. 71.  2005. Liver repair by intra- and extrahepatic progenitors. Stem Cell Rev. 1:61–64 [Google Scholar]
  72. Fausto N. 72.  2004. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39:1477–87 [Google Scholar]
  73. Yanger K, Stanger BZ. 73.  2011. Facultative stem cells in liver and pancreas: fact and fancy. Dev. Dyn. 240:521–29 [Google Scholar]
  74. Saxena R, Theise N. 74.  2004. Canals of Hering: recent insights and current knowledge. Semin. Liver Dis. 24:43–48 [Google Scholar]
  75. Tanimizu N, Miyajima A. 75.  2007. Molecular mechanism of liver development and regeneration. Int. Rev. Cytol. 259:1–48 [Google Scholar]
  76. Miyajima A, Tanaka M, Itoh T. 76.  2014. Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming. Cell Stem Cell 14:561–74 [Google Scholar]
  77. Wang X, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. 77.  2003. The origin and liver repopulating capacity of murine oval cells. Proc. Natl. Acad. Sci. USA 100:Suppl. 111881–88 [Google Scholar]
  78. Wagers AJ, Weissman IL. 78.  2004. Plasticity of adult stem cells. Cell 116:639–48 [Google Scholar]
  79. Tatematsu M, Ho RH, Kaku T, Ekem JK, Farber E. 79.  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]
  80. Evarts RP, Nagy P, Marsden E, Thorgeirsson SS. 80.  1987. A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis 8:1737–40 [Google Scholar]
  81. Michalopoulos GK. 81.  2014. The liver is a peculiar organ when it comes to stem cells. Am. J. Pathol. 184:1263–67 [Google Scholar]
  82. Danielian PS, Muccino D, Rowitch DH, Michael SK, McMahon AP. 82.  1998. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr. Biol. 8:1323–26 [Google Scholar]
  83. Yanger K, Knigin D, Zong Y, Maggs L, Gu G. 83.  et al. 2014. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 15:3340–49 [Google Scholar]
  84. Sackett S, Li Z, Hurtt R, Gao Y, Wells R. 84.  et al. 2009. Foxl1 is a marker of bipotential hepatic progenitor cells in mice. Hepatology 49:920–29 [Google Scholar]
  85. Shin S, Walton G, Aoki R, Brondell K, Schug J. 85.  et al. 2011. Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential. Genes Dev. 25:1185–92 [Google Scholar]
  86. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M. 86.  et al. 2007. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–7 [Google Scholar]
  87. Barker N, Tan S, Clevers H. 87.  2013. Lgr proteins in epithelial stem cell biology. Development 140:2484–94 [Google Scholar]
  88. Huch M, Dorrell C, Boj SF, van Es JH, Li VS. 88.  et al. 2013. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494:247–50 [Google Scholar]
  89. Dorrell C, Erker L, Schug J, Kopp JL, Canaday PS. 89.  et al. 2011. Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev. 25:1193–203 [Google Scholar]
  90. Okabe M, Tsukahara Y, Tanaka M, Suzuki K, Saito S. 90.  et al. 2009. Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse liver. Development 136:1951–60 [Google Scholar]
  91. Kamiya A, Kakinuma S, Yamazaki Y, Nakauchi H. 91.  2009. Enrichment and clonal culture of progenitor cells during mouse postnatal liver development in mice. Gastroenterology 137:1114–26.e14 [Google Scholar]
  92. Suzuki A, Sekiya S, Onishi M, Oshima N, Kiyonari H. 92.  et al. 2008. Flow cytometric isolation and clonal identification of self-renewing bipotent hepatic progenitor cells in adult mouse liver. Hepatology 48:1964–78 [Google Scholar]
  93. Tarlow BD, Finegold MJ, Grompe M. 93.  2014. Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 60:278–89 [Google Scholar]
  94. Choi TY, Ninov N, Stainier DY, Shin D. 94.  2014. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 146:776–88 [Google Scholar]
  95. He J, Lu H, Zou Q, Luo L. 95.  2014. Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 146:789–800 [Google Scholar]
  96. Dor Y, Brown J, Martinez OI, Melton DA. 96.  2004. Adult pancreatic β-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46 [Google Scholar]
  97. Michalopoulos G, Barua L, Bowen W. 97.  2005. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 41:535–44 [Google Scholar]
  98. Sekiya S, Suzuki A. 98.  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]
  99. Tanimizu N, Nishikawa Y, Ichinohe N, Akiyama H, Mitaka T. 99.  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]
  100. Overturf K, al-Dhalimy M, Ou CN, Finegold M, Grompe M. 100.  1997. Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am. J. Pathol. 151:1273–80 [Google Scholar]
  101. Duncan AW, Hanlon Newell AE, Smith L, Wilson EM, Olson SB. 101.  et al. 2012. Frequent aneuploidy among normal human hepatocytes. Gastroenterology 142:25–28 [Google Scholar]
  102. Duncan AW, Taylor MH, Hickey RD, Hanlon Newell AE, Lenzi ML. 102.  et al. 2010. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 467:707–10 [Google Scholar]
  103. Natarajan A, Wagner B, Sibilia M. 103.  2007. The EGF receptor is required for efficient liver regeneration. Proc. Natl. Acad. Sci. USA 104:17081–86 [Google Scholar]
  104. Borowiak M, Garratt AN, Wustefeld T, Strehle M, Trautwein C, Birchmeier C. 104.  2004. Met provides essential signals for liver regeneration. Proc. Natl. Acad. Sci. USA 101:10608–13 [Google Scholar]
  105. Webber EM, Bruix J, Pierce RH, Fausto N. 105.  1998. Tumor necrosis factor primes hepatocytes for DNA replication in the rat. Hepatology 28:1226–34 [Google Scholar]
  106. Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE. 106.  et al. 1996. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274:1379–83 [Google Scholar]
  107. Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J. 107.  et al. 2006. Nuclear receptor–dependent bile acid signaling is required for normal liver regeneration. Science 312:233–36 [Google Scholar]
  108. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C. 108.  et al. 2007. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–43 [Google Scholar]
  109. Limaye PB, Bowen WC, Orr AV, Luo J, Tseng GC, Michalopoulos GK. 109.  2008. Mechanisms of hepatocyte growth factor–mediated and epidermal growth factor–mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium. Hepatology 47:1702–13 [Google Scholar]
  110. Zhao B, Tumaneng K, Guan KL. 110.  2011. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nat. Cell Biol. 13:877–83 [Google Scholar]
  111. Dong J, Feldmann G, Huang J, Wu S, Zhang N. 111.  et al. 2007. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 130:1120–33 [Google Scholar]
  112. Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW. 112.  et al. 2007. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr. Biol. 17:2054–60 [Google Scholar]
  113. Avruch J, Zhou D, Fitamant J, Bardeesy N. 113.  2011. Mst1/2 signalling to Yap: gatekeeper for liver size and tumour development. Br. J. Cancer 104:24–32 [Google Scholar]
  114. Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B. 114.  et al. 2014. Hippo pathway activity influences liver cell fate. Cell 157:1324–38 [Google Scholar]
  115. Takase HM, Itoh T, Ino S, Wang T, Koji T. 115.  et al. 2013. FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration. Genes Dev. 27:169–81 [Google Scholar]
  116. Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR. 116.  et al. 1998. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N. Engl. J. Med. 338:1422–26 [Google Scholar]
  117. DeWard AD, Komori J, Lagasse E. 117.  2014. Ectopic transplantation sites for cell-based therapy. Curr. Opin. Organ Transplant. 19:169–74 [Google Scholar]
  118. Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N. 118.  et al. 2012. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Investig. 122:2911–15 [Google Scholar]
  119. Sekiya S, Suzuki A. 119.  2012. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J. Clin. Investig. 122:3914–18 [Google Scholar]
  120. Villanueva A, Alsinet C, Yanger K, Hoshida Y, Zong Y. 120.  et al. 2012. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 143:1660–69.e7 [Google Scholar]

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