Bile Duct Development and the Notch Signaling Pathway

  • Stacey S. HuppertEmail author
  • Kathleen M. Campbell


Intrahepatic bile duct development is a sophisticated process that begins with a simple, perivenular arrangement of hepatoblasts and ends with an intricate, arborizing, hierarchical network of ducts that navigate the liver parenchyma, contributing to liver health and disease not only via drainage of bile but via direct and indirect interactions with surrounding cells. Development of the intrahepatic bile ducts depends upon cell specification and subsequent morphogenesis, both involving intercellular signaling through the Notch pathway. Alteration of this pathway by mutations in critical Notch ligands and/or Notch receptors disrupts normal intrahepatic bile duct formation and leads to the hepatobiliary phenotype seen in Alagille syndrome. More complete insight into the complexities of intrahepatic bile duct development and the signaling pathways involved (Notch and others) is a requisite preamble to defining cellular and molecular therapies with the potential of attenuating, or reversing, biliary injury in Alagille syndrome and other cholangiopathies.


Bile duct development Biliary system Cholangiocyte Liver Notch Jagged Alagille syndrome 


  1. 1.
    Gissen P, Arias IM. Structural and functional hepatocyte polarity and liver disease. J Hepatol. 2015;63(4):1023–37.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Keppler D. Progress in the molecular characterization of hepatobiliary transporters. Dig Dis. 2017;35(3):197–202.PubMedGoogle Scholar
  3. 3.
    Roskams TA, Theise ND, Balabaud C, Bhagat G, Bhathal PS, Bioulac-Sage P, et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology. 2004;39(6):1739–45.PubMedGoogle Scholar
  4. 4.
    Yoo KS, Lim WT, Choi HS. Biology of Cholangiocytes: from bench to bedside. Gut Liver. 2016;10(5):687–98.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Ramesh Babu CS, Sharma M. Biliary tract anatomy and its relationship with venous drainage. J Clin Exp Hepatol. 2014;4(Suppl 1):S18–26.PubMedGoogle Scholar
  6. 6.
    Lanzoni G, Cardinale V, Carpino G. The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: a new reference frame for disease and regeneration. Hepatology. 2016;64(1):277–86.PubMedGoogle Scholar
  7. 7.
    Baer MM, Chanut-Delalande H, Affolter M. Cellular and molecular mechanisms underlying the formation of biological tubes. Curr Top Dev Biol. 2009;89:137–62.PubMedGoogle Scholar
  8. 8.
    Lemaigre FP. Molecular mechanisms of biliary development. Prog Mol Biol Transl Sci. 2010;97:103–26.PubMedGoogle Scholar
  9. 9.
    Tanimizu N, Mitaka T. Epithelial Morphogenesis during Liver Development. Cold Spring Harb Perspect Biol. 2017;9(8):a027862.PubMedGoogle Scholar
  10. 10.
    Desmet VJ. Ductal plates in hepatic ductular reactions. Hypothesis and implications. II. Ontogenic liver growth in childhood. Virchows Arch. 2011;458(3):261–70.PubMedGoogle Scholar
  11. 11.
    Desmet VJ. Congenital diseases of intrahepatic bile ducts: variations on the theme "ductal plate malformation". Hepatology. 1992;16(4):1069–83.PubMedGoogle Scholar
  12. 12.
    Raynaud P, Tate J, Callens C, Cordi S, Vandersmissen P, Carpentier R, et al. A classification of ductal plate malformations based on distinct pathogenic mechanisms of biliary dysmorphogenesis. Hepatology. 2011;53(6):1959–66.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Terada T. Human ductal plate and its derivatives express antigens of cholangiocellular, hepatocellular, hepatic stellate/progenitor cell, stem cell, and neuroendocrine lineages, and proliferative antigens. Exp Biol Med (Maywood). 2017;242(9):907–17.Google Scholar
  14. 14.
    Van Eyken P, Sciot R, Callea F, Van der Steen K, Moerman P, Desmet VJ. The development of the intrahepatic bile ducts in man: a keratin-immunohistochemical study. Hepatology. 1988;8(6):1586–95.PubMedGoogle Scholar
  15. 15.
    Vestentoft PS, Jelnes P, Hopkinson BM, Vainer B, Mollgard K, Quistorff B, et al. Three-dimensional reconstructions of intrahepatic bile duct tubulogenesis in human liver. BMC Dev Biol. 2011;11:56.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Antoniou A, Raynaud P, Cordi S, Zong Y, Tronche F, Stanger BZ, et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology. 2009;136(7):2325–33.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Carpentier R, Suner RE, van Hul N, Kopp JL, Beaudry JB, Cordi S, et al. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology. 2011;141(4):1432–8. 8 e1–4PubMedPubMedCentralGoogle Scholar
  18. 18.
    Tanimizu N, Miyajima A, Mostov KE. Liver progenitor cells fold up a cell monolayer into a double-layered structure during tubular morphogenesis. Mol Biol Cell. 2009;20(9):2486–94.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Takashima Y, Terada M, Kawabata M, Suzuki A. Dynamic three-dimensional morphogenesis of intrahepatic bile ducts in mouse liver development. Hepatology. 2015;61(3):1003–11.PubMedGoogle Scholar
  20. 20.
    Terada T, Nakanuma Y. Detection of apoptosis and expression of apoptosis-related proteins during human intrahepatic bile duct development. Am J Pathol. 1995;146(1):67–74.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Gerard C, Tys J, Lemaigre FP. Gene regulatory networks in differentiation and direct reprogramming of hepatic cells. Semin Cell Dev Biol. 2017;66:43–50.PubMedGoogle Scholar
  22. 22.
    Kaneko K, Kamimoto K, Miyajima A, Itoh T. Adaptive remodeling of the biliary architecture underlies liver homeostasis. Hepatology. 2015;61(6):2056–66.PubMedGoogle Scholar
  23. 23.
    Tanimizu N, Kaneko K, Itoh T, Ichinohe N, Ishii M, Mizuguchi T, et al. Intrahepatic bile ducts are developed through formation of homogeneous continuous luminal network and its dynamic rearrangement in mice. Hepatology. 2016;64(1):175–88.PubMedGoogle Scholar
  24. 24.
    Colombo F, Armstrong C, Duan J, Rioux N. A high throughput in vitro mrp2 assay to predict in vivo biliary excretion. Xenobiotica. 2012;42(2):157–63.PubMedGoogle Scholar
  25. 25.
    Chiba S. Notch signaling in stem cell systems. Stem Cells. 2006;24(11):2437–47.PubMedGoogle Scholar
  26. 26.
    Kopan R, Ilagan MX. The canonical notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216–33.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the notch signaling pathway. J Cell Physiol. 2003;194(3):237–55.PubMedGoogle Scholar
  28. 28.
    Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol. 2012;23(4):450–7.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Hansson EM, Lendahl U, Chapman G. Notch signaling in development and disease. Semin Cancer Biol. 2004;14(5):320–8.PubMedGoogle Scholar
  30. 30.
    Tikka S, Baumann M, Siitonen M, Pasanen P, Poyhonen M, Myllykangas L, et al. CADASIL and CARASIL. Brain Pathol. 2014;24(5):525–44.PubMedGoogle Scholar
  31. 31.
    Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–71.PubMedGoogle Scholar
  32. 32.
    Turnpenny PD, Alman B, Cornier AS, Giampietro PF, Offiah A, Tassy O, et al. Abnormal vertebral segmentation and the notch signaling pathway in man. Dev Dyn. 2007;236(6):1456–74.PubMedGoogle Scholar
  33. 33.
    Warthen DM, Moore EC, Kamath BM, Morrissette JJ, Sanchez-Lara PA, Piccoli DA, et al. Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Hum Mutat. 2006;27(5):436–43.Google Scholar
  34. 34.
    Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, et al. NOTCH2 mutations in Alagille syndrome. J Med Genet. 2012;49(2):138–44.PubMedGoogle Scholar
  35. 35.
    Kamath BM, Krantz ID, Spinner NB, Heubi JE, Piccoli DA. Monozygotic twins with a severe form of Alagille syndrome and phenotypic discordance. Am J Med Genet. 2002;112(2):194–7.PubMedGoogle Scholar
  36. 36.
    Kamath BM, Munoz PS, Bab N, Baker A, Chen Z, Spinner NB, et al. A longitudinal study to identify laboratory predictors of liver disease outcome in Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;50(5):526–30.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Izumi K, Hayashi D, Grochowski CM, Kubota N, Nishi E, Arakawa M, et al. Discordant clinical phenotype in monozygotic twins with Alagille syndrome: possible influence of non-genetic factors. Am J Med Genet A. 2016;170A(2):471–5.PubMedGoogle Scholar
  38. 38.
    Lin HC, Le Hoang P, Hutchinson A, Chao G, Gerfen J, Loomes KM, et al. Alagille syndrome in a Vietnamese cohort: mutation analysis and assessment of facial features. Am J Med Genet A. 2012;158A(5):1005–13.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development. 2010;137(23):4061–72.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Kodama Y, Hijikata M, Kageyama R, Shimotohno K, Chiba T. The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology. 2004;127(6):1775–86.PubMedGoogle Scholar
  41. 41.
    Tanimizu N, Miyajima A. Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci. 2004;117(Pt 15):3165–74.PubMedGoogle Scholar
  42. 42.
    McCright B, Lozier J, Gridley T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development. 2002;129(4):1075–82.PubMedGoogle Scholar
  43. 43.
    McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, et al. Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation. Development. 2001;128(4):491–502.Google Scholar
  44. 44.
    Xue Y, Gao X, Lindsell CE, Norton CR, Chang B, Hicks C, et al. Embryonic lethality and vascular defects in mice lacking the notch ligand Jagged1. Hum Mol Genet. 1999;8(5):723–30.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Loomes KM, Russo P, Ryan M, Nelson A, Underkoffler L, Glover C, et al. Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage. Hepatology. 2007;45(2):323–30.PubMedGoogle Scholar
  46. 46.
    Thakurdas SM, Lopez MF, Kakuda S, Fernandez-Valdivia R, Zarrin-Khameh N, Haltiwanger RS, et al. Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology. 2016;63(2):550–65.PubMedGoogle Scholar
  47. 47.
    Zong Y, Panikkar A, Xu J, Antoniou A, Raynaud P, Lemaigre F, et al. Notch signaling controls liver development by regulating biliary differentiation. Development. 2009;136(10):1727–39.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29(3):822–9.PubMedGoogle Scholar
  49. 49.
    Sparks EE, Huppert KA, Brown MA, Washington MK, Huppert SS. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology. 2010;51(4):1391–400.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Kellendonk C, Opherk C, Anlag K, Schutz G, Tronche F. Hepatocyte-specific expression of Cre recombinase. Genesis. 2000;26(2):151–3.PubMedGoogle Scholar
  51. 51.
    Falix FA, Weeda VB, Labruyere WT, Poncy A, de Waart DR, Hakvoort TB, et al. Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning. Dev Biol. 2014;396(2):201–13.PubMedGoogle Scholar
  52. 52.
    Jeliazkova P, Jors S, Lee M, Zimber-Strobl U, Ferrer J, Schmid RM, et al. Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1. Hepatology. 2013;57(6):2469–79.PubMedGoogle Scholar
  53. 53.
    Tchorz JS, Kinter J, Muller M, Tornillo L, Heim MH, Bettler B. Notch2 signaling promotes biliary epithelial cell fate specification and tubulogenesis during bile duct development in mice. Hepatology. 2009;50(3):871–9.PubMedGoogle Scholar
  54. 54.
    Postic C, Magnuson MA. DNA excision in liver by an albumin-Cre transgene occurs progressively with age. Genesis. 2000;26(2):149–50.PubMedGoogle Scholar
  55. 55.
    Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U, Strobl LJ, et al. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology. 2008;48(2):607–16.PubMedGoogle Scholar
  56. 56.
    Lozier J, McCright B, Gridley T. Notch signaling regulates bile duct morphogenesis in mice. PLoS One. 2008;3(3):e1851.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Conlon RA, Reaume AG, Rossant J. Notch1 is required for the coordinate segmentation of somites. Development. 1995;121(5):1533–45.PubMedGoogle Scholar
  58. 58.
    Hamada Y, Kadokawa Y, Okabe M, Ikawa M, Coleman JR, Tsujimoto Y. Mutation in ankyrin repeats of the mouse Notch2 gene induces early embryonic lethality. Development. 1999;126(15):3415–24.PubMedGoogle Scholar
  59. 59.
    Huppert SS, Le A, Schroeter EH, Mumm JS, Saxena MT, Milner LA, et al. Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1. Nature. 2000;405(6789):966–70.PubMedGoogle Scholar
  60. 60.
    Swiatek PJ, Lindsell CE, del Amo FF, Weinmaster G, Gridley T. Notch1 is essential for postimplantation development in mice. Genes Dev. 1994;8(6):707–19.PubMedGoogle Scholar
  61. 61.
    Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, et al. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev. 2000;14(11):1343–52.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Krebs LT, Xue Y, Norton CR, Sundberg JP, Beatus P, Lendahl U, et al. Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation. Genesis. 2003;37(3):139–43.PubMedGoogle Scholar
  63. 63.
    Pan Y, Lin MH, Tian X, Cheng HT, Gridley T, Shen J, et al. Gamma-secretase functions through notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell. 2004;7(5):731–43.PubMedGoogle Scholar
  64. 64.
    Ortica S, Tarantino N, Aulner N, Israel A, Gupta-Rossi N. The 4 notch receptors play distinct and antagonistic roles in the proliferation and hepatocytic differentiation of liver progenitors. FASEB J. 2014;28(2):603–14.PubMedGoogle Scholar
  65. 65.
    James AC, Szot JO, Iyer K, Major JA, Pursglove SE, Chapman G, et al. Notch4 reveals a novel mechanism regulating notch signal transduction. Biochim Biophys Acta. 2014;1843(7):1272–84.PubMedGoogle Scholar
  66. 66.
    Carulli AJ, Keeley TM, Demitrack ES, Chung J, Maillard I, Samuelson LC. Notch receptor regulation of intestinal stem cell homeostasis and crypt regeneration. Dev Biol. 2015;402(1):98–108.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Shih HP, Kopp JL, Sandhu M, Dubois CL, Seymour PA, Grapin-Botton A, et al. A notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development. 2012;139(14):2488–99.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Gama-Norton L, Ferrando E, Ruiz-Herguido C, Liu Z, Guiu J, Islam AB, et al. Notch signal strength controls cell fate in the haemogenic endothelium. Nat Commun. 2015;6:8510.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Goentoro L, Kirschner MW. Evidence that fold-change, and not absolute level, of beta-catenin dictates Wnt signaling. Mol Cell. 2009;36(5):872–84.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Libbrecht L, Spinner NB, Moore EC, Cassiman D, Van Damme-Lombaerts R, Roskams T. Peripheral bile duct paucity and cholestasis in the liver of a patient with Alagille syndrome: further evidence supporting a lack of postnatal bile duct branching and elongation. Am J Surg Pathol. 2005;29(6):820–6.PubMedGoogle Scholar
  71. 71.
    Subramaniam P, Knisely A, Portmann B, Qureshi SA, Aclimandos WA, Karani JB, et al. Diagnosis of Alagille syndrome-25 years of experience at King's college hospital. J Pediatr Gastroenterol Nutr. 2011;52(1):84–9.PubMedGoogle Scholar
  72. 72.
    Dahms BB, Petrelli M, Wyllie R, Henoch MS, Halpin TC, Morrison S, et al. Arteriohepatic dysplasia in infancy and childhood: a longitudinal study of six patients. Hepatology. 1982;2(3):350–8.PubMedGoogle Scholar
  73. 73.
    Kahn EI, Daum F, Markowitz J, Aiges HW, Schneider KM, So HB, et al. Arteriohepatic dysplasia. II Hepatobiliary morphology Hepatology. Hepatology. 1983;3(1):77–84.PubMedGoogle Scholar
  74. 74.
    Rapp JB, Bellah RD, Maya C, Pawel BR, Anupindi SA. Giant hepatic regenerative nodules in Alagille syndrome. Pediatr Radiol. 2017;47(2):197–204.PubMedGoogle Scholar
  75. 75.
    Alhammad A, Kamath BM, Chami R, Ng VL, Chavhan GB. Solitary hepatic nodule adjacent to the right portal vein: a common finding of Alagille syndrome? J Pediatr Gastroenterol Nutr. 2016;62(2):226–32.PubMedGoogle Scholar
  76. 76.
    Suzuki K, Tanaka M, Watanabe N, Saito S, Nonaka H, Miyajima A. p75 Neurotrophin receptor is a marker for precursors of stellate cells and portal fibroblasts in mouse fetal liver. Gastroenterology. 2008;135(1):270–81. e3PubMedGoogle Scholar
  77. 77.
    Kaylan KB, Ermilova V, Yada RC, Underhill GH. Combinatorial microenvironmental regulation of liver progenitor differentiation by notch ligands, TGFbeta, and extracellular matrix. Sci Rep. 2016;6:23490.PubMedPubMedCentralGoogle Scholar
  78. 78.
    del Alamo D, Rouault H, Schweisguth F. Mechanism and significance of cis-inhibition in notch signalling. Curr Biol. 2011;21(1):R40–7.PubMedGoogle Scholar
  79. 79.
    de Celis JF, Bray S. Feed-back mechanisms affecting notch activation at the dorsoventral boundary in the Drosophila wing. Development. 1997;124(17):3241–51.PubMedGoogle Scholar
  80. 80.
    Jacobsen TL, Brennan K, Arias AM, Muskavitch MA. Cis-interactions between Delta and notch modulate neurogenic signalling in Drosophila. Development. 1998;125(22):4531–40.PubMedGoogle Scholar
  81. 81.
    Klein T, Brennan K, Arias AM. An intrinsic dominant negative activity of serrate that is modulated during wing development in Drosophila. Dev Biol. 1997;189(1):123–34.PubMedGoogle Scholar
  82. 82.
    Micchelli CA, Rulifson EJ, Blair SS. The function and regulation of cut expression on the wing margin of Drosophila: notch, wingless and a dominant negative role for Delta and serrate. Development. 1997;124(8):1485–95.PubMedGoogle Scholar
  83. 83.
    Formosa-Jordan P, Ibanes M. Competition in notch signaling with cis enriches cell fate decisions. PLoS One. 2014;9(4):e95744.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Walter TJ, Vanderpool C, Cast AE, Huppert SS. Intrahepatic bile duct regeneration in mice does not require Hnf6 or notch signaling through Rbpj. Am J Pathol. 2014;184(5):1479–88.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Vanderpool C, Sparks EE, Huppert KA, Gannon M, Means AL, Huppert SS. Genetic interactions between hepatocyte nuclear factor-6 and notch signaling regulate mouse intrahepatic bile duct development in vivo. Hepatology. 2012;55(1):233–43.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Ernst LM, Spinner NB, Piccoli DA, Mauger J, Russo P. Interlobular bile duct loss in pediatric cholestatic disease is associated with aberrant cytokeratin 7 expression by hepatocytes. Pediatr Dev Pathol. 2007;10(5):383–90.PubMedGoogle Scholar
  87. 87.
    Fabris L, Cadamuro M, Guido M, Spirli C, Fiorotto R, Colledan M, et al. Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling. Am J Pathol. 2007;171(2):641–53.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Fukuda K, Sugihara A, Nakasho K, Tsujimura T, Yamada N, Okaya A, et al. The origin of biliary ductular cells that appear in the spleen after transplantation of hepatocytes. Cell Transplant. 2004;13(1):27–33.PubMedGoogle Scholar
  89. 89.
    Limaye PB, Alarcon G, Walls AL, Nalesnik MA, Michalopoulos GK, Demetris AJ, et al. Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development. Lab Investig. 2008;88(8):865–72.PubMedGoogle Scholar
  90. 90.
    Michalopoulos GK, Barua L, Bowen WC. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology. 2005;41(3):535–44.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Sekiya S, Suzuki A. Hepatocytes, rather than cholangiocytes, can be the major source of primitive ductules in the chronically injured mouse liver. Am J Pathol. 2014;184(5):1468–78.PubMedGoogle Scholar
  92. 92.
    Tanimizu N, Nishikawa Y, Ichinohe N, Akiyama H, Mitaka T. 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. 2014;289(11):7589–98.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Tarlow BD, Pelz C, Naugler WE, Wakefield L, Wilson EM, Finegold MJ, et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell. 2014;15(5):605–18.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Yanger K, Zong Y, Maggs LR, Shapira SN, Maddipati R, Aiello NM, et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 2013;27(7):719–24.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, et al. Hippo pathway activity influences liver cell fate. Cell. 2014;157(6):1324–38.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Fiorotto R, Raizner A, Morell CM, Torsello B, Scirpo R, Fabris L, et al. Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. J Hepatol. 2013;59(1):124–30.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Clotman F, Jacquemin P, Plumb-Rudewiez N, Pierreux CE, Van der Smissen P, Dietz HC, et al. Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes Dev. 2005;19(16):1849–54.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Takayama K, Kawabata K, Nagamoto Y, Inamura M, Ohashi K, Okuno H, et al. CCAAT/enhancer binding protein-mediated regulation of TGFbeta receptor 2 expression determines the hepatoblast fate decision. Development. 2014;141(1):91–100.PubMedGoogle Scholar
  99. 99.
    Cordi S, Godard C, Saandi T, Jacquemin P, Monga SP, Colnot S, et al. Role of beta-catenin in development of bile ducts. Differentiation. 2016;91(1–3):42–9.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S, et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest. 2012;122(8):2911–5.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Limaye PB, Bowen WC, Orr AV, Luo J, Tseng GC, Michalopoulos GK. Mechanisms of hepatocyte growth factor-mediated and epidermal growth factor-mediated signaling in transdifferentiation of rat hepatocytes to biliary epithelium. Hepatology. 2008;47(5):1702–13.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Sekiya S, Suzuki A. Intrahepatic cholangiocarcinoma can arise from notch-mediated conversion of hepatocytes. J Clin Invest. 2012;122(11):3914–8.PubMedPubMedCentralGoogle Scholar
  103. 103.
    High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA. Endothelial expression of the notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci U S A. 2008;105(6):1955–9.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Chillakuri CR, Sheppard D, Ilagan MX, Holt LR, Abbott F, Liang S, et al. Structural analysis uncovers lipid-binding properties of notch ligands. Cell Rep. 2013;5(4):861–7.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Luca VC, Kim BC, Ge C, Kakuda S, Wu D, Roein-Peikar M, et al. Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science. 2017;355(6331):1320–4.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Kovall RA, Gebelein B, Sprinzak D, Kopan R. The canonical notch signaling pathway: structural and biochemical insights into shape, sugar, and force. Dev Cell. 2017;41(3):228–41.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Gastroenterology Hepatology and NutritionCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  2. 2.Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiUSA

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