Intrahepatic bile duct regeneration in mice does not require Hnf6 or notch signaling through Rbpj

Teagan J. Walter, Charles Vanderpool, Ashley E. Cast, Stacey S. Huppert

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 Hnf6flox/flox Rbpjflox/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 Hnf6flox/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.

Original languageEnglish (US)
Pages (from-to)1479-1488
Number of pages10
JournalAmerican Journal of Pathology
Volume184
Issue number5
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Intrahepatic Bile Ducts
Regeneration
Liver
Epithelial Cells
Bile Ducts
Albumins
Bile Duct Diseases
Alagille Syndrome
Hepatic Insufficiency
Morphogenesis
Liver Diseases
Hepatocytes
Pediatrics
Phenotype
Mutation
Serum

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Intrahepatic bile duct regeneration in mice does not require Hnf6 or notch signaling through Rbpj. / Walter, Teagan J.; Vanderpool, Charles; Cast, Ashley E.; Huppert, Stacey S.

In: American Journal of Pathology, Vol. 184, No. 5, 2014, p. 1479-1488.

Research output: Contribution to journalArticle

Walter, Teagan J. ; Vanderpool, Charles ; Cast, Ashley E. ; Huppert, Stacey S. / Intrahepatic bile duct regeneration in mice does not require Hnf6 or notch signaling through Rbpj. In: American Journal of Pathology. 2014 ; Vol. 184, No. 5. pp. 1479-1488.
@article{194c668b458e45b186403e784161960c,
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 Hnf6flox/flox Rbpjflox/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 Hnf6flox/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.",
author = "Walter, {Teagan J.} and Charles Vanderpool and Cast, {Ashley E.} and Huppert, {Stacey S.}",
year = "2014",
doi = "10.1016/j.ajpath.2014.01.030",
language = "English (US)",
volume = "184",
pages = "1479--1488",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - Intrahepatic bile duct regeneration in mice does not require Hnf6 or notch signaling through Rbpj

AU - Walter, Teagan J.

AU - Vanderpool, Charles

AU - Cast, Ashley E.

AU - Huppert, Stacey S.

PY - 2014

Y1 - 2014

N2 - 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 Hnf6flox/flox Rbpjflox/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 Hnf6flox/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.

AB - 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 Hnf6flox/flox Rbpjflox/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 Hnf6flox/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.

UR - http://www.scopus.com/inward/record.url?scp=84899554175&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899554175&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2014.01.030

DO - 10.1016/j.ajpath.2014.01.030

M3 - Article

VL - 184

SP - 1479

EP - 1488

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 5

ER -