Regeneration Defects in Yap and Taz Mutant Mouse Livers are Caused by Bile Duct Disruption and Cholestasis

Elisabeth Verboven, Iván M Moya, Leticia Sansores-Garcia, Jun Xie, Hanne Hillen, Weronika Kowalczyk, Gerlanda Vella, Stefaan Verhulst, Stéphanie A Castaldo, Ana Algueró-Nadal, Lucia Romanelli, Cristina Mercader-Celma, Natália A Souza, Soheil Soheily, Leen van Huffel, Thomas Van Brussel, Diether Lambrechts, Tania Roskams, Frédéric P Lemaigre, Gabrielle BergersLeo A van Grunsven, Georg Halder

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2 Citaten (Scopus)

Samenvatting

BACKGROUND AND AIMS: The Hippo pathway and its downstream effectors YAP and TAZ (YAP/TAZ) are heralded as important regulators of organ growth and regeneration. However, different studies provided contradictory conclusions about their role during regeneration of different organs ranging from promoting proliferation to inhibiting it. Here, we resolve the function of YAP/TAZ during regeneration of the liver, where Hippo's role in growth control has been studied most intensely.

METHODS: We evaluated liver regeneration after CCl4 toxic liver injury in mice with conditional deletion of Yap/Taz in hepatocytes and/or biliary epithelial cells and measured the behavior of different cell types during regeneration by histology, RNA-sequencing and flow cytometry.

RESULTS: We found that YAP/TAZ were activated in hepatocytes in response to CCl4 toxic injury. However, their targeted deletion in adult hepatocytes did not noticeably impair liver regeneration. In contrast, Yap/Taz deletion in adult bile ducts caused severe defects and delay in liver regeneration. Mechanistically, we show that Yap/Taz mutant bile ducts degenerated, causing cholestasis which stalled the recruitment of phagocytic macrophages and the removal of cellular corpses from injury sites. Elevated bile acids activated PXR, which was sufficient to recapitulate the phenotype observed in mutant mice.

CONCLUSIONS: Our data show that YAP/TAZ are practically dispensable in hepatocytes for liver development and regeneration. Rather, YAP/TAZ play an indirect role in liver regeneration by preserving bile duct integrity and securing immune cell recruitment and function.

Originele taal-2English
Pagina's (van-tot)847-862
Aantal pagina's16
TijdschriftGastroenterology
Volume160
Nummer van het tijdschrift3
Vroegere onlinedatum2020
DOI's
StatusPublished - feb 2021

Bibliografische nota

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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