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Spontaneous repopulation of β‐catenin null livers with β‐catenin‐positive hepatocytes after chronic murine liver injury
Author(s) -
Thompson Michael D.,
Wickline Emily D.,
Bowen William B.,
Lu Amy,
Singh Sucha,
Misse Amalea,
Monga Satdarshan P.S.
Publication year - 2011
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.24506
Subject(s) - hepatocyte , fibrosis , catenin , progenitor cell , biology , liver injury , beta catenin , medicine , pathology , endocrinology , stem cell , wnt signaling pathway , microbiology and biotechnology , genetics , signal transduction , in vitro
Prolonged exposure of mice to diet containing 0.1% 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) results in hepatobiliary injury, atypical ductular proliferation, oval cell appearance, and limited fibrosis. Previously, we reported that short‐term ingestion of DDC diet by hepatocyte‐specific β‐catenin conditional knockout (KO) mice led to fewer A6‐positive oval cells than wildtype (WT) littermates. To examine the role of β‐catenin in chronic hepatic injury and repair, we exposed WT and KO mice to DDC for 80 and 150 days. Paradoxically, long‐term DDC exposure led to significantly more A6‐positive cells, indicating greater atypical ductular proliferation in KO, which coincided with increased fibrosis and cholestasis. Surprisingly, at 80 and 150 days in KO we observed a significant amelioration of hepatocyte injury. This coincided with extensive repopulation of β‐catenin null livers with β‐catenin‐positive hepatocytes at 150 days, which was preceded by appearance of β‐catenin‐positive hepatocyte clusters at 80 days and a few β‐catenin‐positive hepatocytes at earlier times. Intriguingly, occasional β‐catenin‐positive hepatocytes that were negative for progenitor markers were also observed at baseline in the KO livers, suggesting spontaneous escape from cre‐mediated recombination. These cells with hepatocyte morphology expressed mature hepatocyte markers but lacked markers of hepatic progenitors. The gradual repopulation of KO livers with β‐catenin‐positive hepatocytes occurred only following DDC injury and coincided with a progressive loss of hepatic cre‐recombinase expression. A few β‐catenin‐positive cholangiocytes were observed albeit only after long‐term DDC exposure and trailed the appearance of β‐catenin‐positive hepatocytes. Conclusion: In a chronic liver injury model, β‐catenin‐positive hepatocytes exhibit growth and survival advantages and repopulate KO livers, eventually limiting hepatic injury and dysfunction despite increased fibrosis and intrahepatic cholestasis. (H EPATOLOGY 2011;)