title: Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj.
abstract: The potential for intrahepatic bile duct (IHBD) regeneration in patients with bile duct insufficiency diseases is poorly understood. Notch signaling and Hnf6 have each been shown to be important for the morphogenesis of IHBDs in mice. One congenital pediatric liver disease characterized by reduced numbers of IHBDs, Alagille syndrome, is associated with mutations in Notch signaling components. Therefore, we investigated whether liver cell plasticity could contribute to IHBD regeneration in mice with disruptions in Notch signaling and Hnf6. We studied a mouse model of bile duct insufficiency with liver epithelial cell-specific deficiencies in Hnf6 and Rbpj, a mediator of canonical Notch signaling. Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice initially developed no peripheral bile ducts. The evolving postnatal liver phenotype was analyzed using IHBD resin casting, immunostaining, and serum chemistry. With age, Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice mounted a ductular reaction extending through the hepatic tissue and then regenerated communicating peripheral IHBD branches. Rbpj and Hnf6 were determined to remain absent from biliary epithelial cells constituting the ductular reaction and the regenerated peripheral IHBDs. We report the expression of Sox9, a marker of biliary epithelial cells, in cells expressing hepatocyte markers. Tissue analysis indicates that reactive ductules did not arise directly from preexisting hilar IHBDs. We conclude that liver cell plasticity is competent for regeneration of IHBDs independent of Notch signaling via Rbpj and Hnf6.
authors.affiliation: Divisions of Gastroenterology, Hepatology, and Nutrition and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Teagan J
authors.initials: TJ
authors.lastname: Walter
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Charles
authors.initials: C
authors.lastname: Vanderpool
authors.affiliation: Divisions of Gastroenterology, Hepatology, and Nutrition and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Cast
authors.affiliation: Divisions of Gastroenterology, Hepatology, and Nutrition and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: stacey.huppert@cchmc.org.
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Huppert
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D051559:Hepatocyte Nuclear Factor 6 / Q000172:deficiency / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D021621:Imaging, Three-Dimensional; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000378:metabolism*; D007150:Immunohistochemistry; D053539:Keratin-19 / Q000378:metabolism; D018345:Mice, Knockout; D037121:Plant Lectins / Q000378:metabolism; D011169:Portal Vein / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D055758:SOX9 Transcription Factor / Q000378:metabolism
chemical_list: D051559:Hepatocyte Nuclear Factor 6; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D053539:Keratin-19; C496606:Onecut1 protein, mouse; D037121:Plant Lectins; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D055758:SOX9 Transcription Factor; C036554:dolichos biflorus agglutinin