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24.01.2021 | Original Article

GATA6 modulates the ductular reaction to bile duct ligation

verfasst von: Marjut Pihlajoki, Tea Soini, Rebecca B. Cochran, Emmi Liljeström, Jiansheng Huang, David A. Rudnick, Dennis J. Dietzen, Antti Kyrönlahti, Mikko P. Pakarinen, Markku Heikinheimo, David B. Wilson

Erschienen in: Hepatology International | Ausgabe 1/2021

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Abstract

Background

GATA6, a transcription factor expressed in cholangiocytes, has been implicated in the response to liver injury. In biliary atresia, a disease characterized by extrahepatic bile duct obstruction, liver expression of GATA6 increases with pathological bile duct expansion and decreases after successful Kasai portoenterostomy. The aim of this study was to garner genetic evidence that GATA6 is involved in ductular formation/expansion.

Methods

The murine Gata6 gene was conditionally deleted using Alb-cre, a transgene expressed in hepatoblasts (the precursors of hepatocytes and cholangiocytes) and mature hepatocytes. Bile duct ligation (BDL) was used to model biliary obstruction.

Results

Alb-Cre;Gata6^flox/flox mice were viable and fertile. Cre-mediated recombination of Gata6 in hepatocytes had little impact on cellular structure or function. GATA6 immunoreactivity was retained in a majority of biliary epithelial cells in adult Alb-Cre;Gata6^flox/flox mice, implying that surviving cholangiocytes were derived from hepatoblasts that had escaped biallelic Cre-mediated recombination. Although GATA6 immunoreactivity was preserved in cholangiocytes, Alb-cre;Gata6^flox/flox mice had a demonstrable biliary phenotype. A neutrophil-rich infiltrate surrounded newly formed bile ducts in neonatal Alb-Cre;Gata6^flox/flox mice. Foci of fibrosis/necrosis, presumed to reflect patchy defects in bile duct formation, were observed in the livers of 37% of adult Alb-cre;Gata6^flox/flox mice and 0% of controls (p < 0.05). Most notably, Alb-cre;Gata6^flox/flox mice had an altered response to BDL manifest as reduced survival, impaired bile ductule proliferation, increased parenchymal necrosis, reduced fibrosis, and enhanced macrophage accumulation in the portal space.

Conclusions

GATA6 orchestrates intrahepatic biliary remodeling and mitigates liver injury following extrahepatic bile duct obstruction.

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Titel: GATA6 modulates the ductular reaction to bile duct ligation
verfasst von: Marjut Pihlajoki
Tea Soini
Rebecca B. Cochran
Emmi Liljeström
Jiansheng Huang
David A. Rudnick
Dennis J. Dietzen
Antti Kyrönlahti
Mikko P. Pakarinen
Markku Heikinheimo
David B. Wilson
Publikationsdatum: 24.01.2021
Verlag: Springer India
Erschienen in: Hepatology International / Ausgabe 1/2021
Print ISSN: 1936-0533
Elektronische ISSN: 1936-0541
DOI: https://doi.org/10.1007/s12072-020-10119-w

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Abstract

Background

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