| First Author | Thompson MD | Year | 2011 |
| Journal | Hepatology | Volume | 54 |
| Issue | 4 | Pages | 1333-43 |
| PubMed ID | 21721031 | Mgi Jnum | J:234602 |
| Mgi Id | MGI:5790310 | Doi | 10.1002/hep.24506 |
| Citation | Thompson MD, et al. (2011) Spontaneous repopulation of beta-catenin null livers with beta-catenin-positive hepatocytes after chronic murine liver injury. Hepatology 54(4):1333-43 |
| abstractText | 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 beta-catenin conditional knockout (KO) mice led to fewer A6-positive oval cells than wildtype (WT) littermates. To examine the role of beta-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 beta-catenin null livers with beta-catenin-positive hepatocytes at 150 days, which was preceded by appearance of beta-catenin-positive hepatocyte clusters at 80 days and a few beta-catenin-positive hepatocytes at earlier times. Intriguingly, occasional beta-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 beta-catenin-positive hepatocytes occurred only following DDC injury and coincided with a progressive loss of hepatic cre-recombinase expression. A few beta-catenin-positive cholangiocytes were observed albeit only after long-term DDC exposure and trailed the appearance of beta-catenin-positive hepatocytes. CONCLUSION: In a chronic liver injury model, beta-catenin-positive hepatocytes exhibit growth and survival advantages and repopulate KO livers, eventually limiting hepatic injury and dysfunction despite increased fibrosis and intrahepatic cholestasis. |
