Spontaneous repopulation of β-catenin null livers with β-catenin-positive hepatocytes after chronic murine liver injury
✍ Scribed by Michael D. Thompson; Emily D. Wickline; William B. Bowen; Amy Lu; Sucha Singh; Amalea Misse; Satdarshan P.S. Monga
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 883 KB
- Volume
- 54
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
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.