Spontaneous repopulation of β-catenin null livers with β-catenin-positive hepatocytes after chronic murine liver injury

Michael D. Thompson, Emily D. Wickline, William B. Bowen, Amy Lu, Sucha Singh, Amalea Misse, Satdarshan P.S. Monga

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1333-1343
Number of pages11
JournalHepatology
Volume54
Issue number4
DOIs
StatePublished - Oct 1 2011
Externally publishedYes

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