WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis

We previously identified an up‐regulation of specific Wnt proteins in the cholangiocyte compartment during cholestatic liver injury and found that mice lacking Wnt secretion from hepatocytes and cholangiocytes showed fewer proliferating cholangiocytes and high mortality in response to a 3,5‐diethoxy...

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Autores principales:	Karis Kosar, Pamela Cornuet, Sucha Singh, Elizabeth Lee, Silvia Liu, Jenesis Gayden, Toshifumi Sato, Zachary Freyberg, Gavin Arteel, Kari Nejak‐Bowen
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/c151200c32814023a236e26d6f6575c4
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spelling	oai:doaj.org-article:c151200c32814023a236e26d6f6575c42021-11-30T13:39:17ZWNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis2471-254X10.1002/hep4.1784https://doaj.org/article/c151200c32814023a236e26d6f6575c42021-12-01T00:00:00Zhttps://doi.org/10.1002/hep4.1784https://doaj.org/toc/2471-254XWe previously identified an up‐regulation of specific Wnt proteins in the cholangiocyte compartment during cholestatic liver injury and found that mice lacking Wnt secretion from hepatocytes and cholangiocytes showed fewer proliferating cholangiocytes and high mortality in response to a 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) diet, a murine model of primary sclerosing cholangitis. In vitro studies demonstrated that Wnt7b, one of the Wnts up‐regulated during cholestasis, induces proliferation of cholangiocytes in an autocrine manner and increases secretion of proinflammatory cytokines. We hypothesized that loss of Wnt7b may exacerbate some of the complications of cholangiopathies by decreasing the ability of bile ducts to induce repair. Wnt7b‐flox mice were bred with Krt19‐cre mice to deplete Wnt7b expression in only cholangiocytes (CC) or with albumin‐Cre mice to delete Wnt7b expression in both hepatocytes and cholangiocytes (HC + CC). These mice were placed on a DDC diet for 1 month then killed for evaluation. Contrary to our expectations, we found that mice lacking Wnt7b from CC and HC + CC compartments had improved biliary injury, decreased cellular senescence, and lesser bile acid accumulation after DDC exposure compared to controls, along with decreased expression of inflammatory cytokines. Although Wnt7b knockout (KO) resulted in fewer proliferating cholangiocytes, CC and HC + CC KO mice on a DDC diet also had more hepatocytes expressing cholangiocyte markers compared to wild‐type mice on a DDC diet, indicating that Wnt7b suppression promotes hepatocyte reprogramming. Conclusion: Wnt7b induces a proproliferative proinflammatory program in cholangiocytes, and its loss is compensated for by conversion of hepatocytes to a biliary phenotype during cholestatic injury.Karis KosarPamela CornuetSucha SinghElizabeth LeeSilvia LiuJenesis GaydenToshifumi SatoZachary FreybergGavin ArteelKari Nejak‐BowenWileyarticleDiseases of the digestive system. GastroenterologyRC799-869ENHepatology Communications, Vol 5, Iss 12, Pp 2019-2034 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Diseases of the digestive system. Gastroenterology RC799-869 Karis Kosar Pamela Cornuet Sucha Singh Elizabeth Lee Silvia Liu Jenesis Gayden Toshifumi Sato Zachary Freyberg Gavin Arteel Kari Nejak‐Bowen WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis
description	We previously identified an up‐regulation of specific Wnt proteins in the cholangiocyte compartment during cholestatic liver injury and found that mice lacking Wnt secretion from hepatocytes and cholangiocytes showed fewer proliferating cholangiocytes and high mortality in response to a 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) diet, a murine model of primary sclerosing cholangitis. In vitro studies demonstrated that Wnt7b, one of the Wnts up‐regulated during cholestasis, induces proliferation of cholangiocytes in an autocrine manner and increases secretion of proinflammatory cytokines. We hypothesized that loss of Wnt7b may exacerbate some of the complications of cholangiopathies by decreasing the ability of bile ducts to induce repair. Wnt7b‐flox mice were bred with Krt19‐cre mice to deplete Wnt7b expression in only cholangiocytes (CC) or with albumin‐Cre mice to delete Wnt7b expression in both hepatocytes and cholangiocytes (HC + CC). These mice were placed on a DDC diet for 1 month then killed for evaluation. Contrary to our expectations, we found that mice lacking Wnt7b from CC and HC + CC compartments had improved biliary injury, decreased cellular senescence, and lesser bile acid accumulation after DDC exposure compared to controls, along with decreased expression of inflammatory cytokines. Although Wnt7b knockout (KO) resulted in fewer proliferating cholangiocytes, CC and HC + CC KO mice on a DDC diet also had more hepatocytes expressing cholangiocyte markers compared to wild‐type mice on a DDC diet, indicating that Wnt7b suppression promotes hepatocyte reprogramming. Conclusion: Wnt7b induces a proproliferative proinflammatory program in cholangiocytes, and its loss is compensated for by conversion of hepatocytes to a biliary phenotype during cholestatic injury.
format	article
author	Karis Kosar Pamela Cornuet Sucha Singh Elizabeth Lee Silvia Liu Jenesis Gayden Toshifumi Sato Zachary Freyberg Gavin Arteel Kari Nejak‐Bowen
author_facet	Karis Kosar Pamela Cornuet Sucha Singh Elizabeth Lee Silvia Liu Jenesis Gayden Toshifumi Sato Zachary Freyberg Gavin Arteel Kari Nejak‐Bowen
author_sort	Karis Kosar
title	WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis
title_short	WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis
title_full	WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis
title_fullStr	WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis
title_full_unstemmed	WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis
title_sort	wnt7b regulates cholangiocyte proliferation and function during murine cholestasis
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/c151200c32814023a236e26d6f6575c4
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WNT7B Regulates Cholangiocyte Proliferation and Function During Murine Cholestasis

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