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Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice
Author(s) -
Okabe Hirohisa,
Yang Jing,
Sylakowski Kyle,
Yovchev Mladen,
Miyagawa Yoshitaka,
Nagarajan Shanmugam,
Chikina Maria,
Thompson Michael,
Oertel Michael,
Baba Hideo,
Monga Satdarshan P,
NejakBowen Kari Nichole
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28774
Subject(s) - wnt signaling pathway , cholangiocyte , transdifferentiation , hepatocyte , biology , microbiology and biotechnology , liver injury , beta catenin , cancer research , signal transduction , stem cell , endocrinology , genetics , in vitro
Hepatic repair is directed chiefly by the proliferation of resident mature epithelial cells. Furthermore, if predominant injury is to cholangiocytes, the hepatocytes can transdifferentiate to cholangiocytes to assist in the repair and vice versa, as shown by various fate‐tracing studies. However, the molecular bases of reprogramming remain elusive. Using two models of biliary injury where repair occurs through cholangiocyte proliferation and hepatocyte transdifferentiation to cholangiocytes, we identify an important role of Wnt signaling. First we identify up‐regulation of specific Wnt proteins in the cholangiocytes. Next, using conditional knockouts of Wntless and Wnt coreceptors low‐density lipoprotein‐related protein 5/6, transgenic mice expressing stable β‐catenin, and in vitro studies, we show a role of Wnt signaling through β‐catenin in hepatocyte to biliary transdifferentiation. Last, we show that specific Wnts regulate cholangiocyte proliferation, but in a β‐catenin‐independent manner. Conclusion: Wnt signaling regulates hepatobiliary repair after cholestatic injury in both β‐catenin‐dependent and ‐independent manners. (H epatology 2016;64:1652‐1666)