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Hepatocyte‐Specific β‐catenin Deletion During Severe Liver Injury Provokes Cholangiocytes to Differentiate into Hepatocytes

Treatments for chronic liver disease are limited due to incomplete understanding of hepatobiliary repair mechanisms. Typically, hepatocytes proliferate to mediate liver regeneration. However, if hepatic injury occurs concomitantly with impairment of hepatocyte proliferation, biliary epithelial cells (BECs) are activated to mediate regeneration by differentiating into hepatocytes. The choline‐deficient ethionine‐supplemented (CDE) diet model of liver injury is known to induce proliferation of BECs, but does not block hepatocyte proliferation. β‐catenin signaling plays an important role in liver regeneration by promoting hepatocyte proliferation. Therefore, we hypothesized that β‐catenin loss in hepatocytes would impair hepatocyte proliferation and lead to BEC‐mediated hepatic repair in the CDE diet model. Indeed, mice with deletion of β‐catenin in both BECs and hepatocytes (KO1 mice) displayed severe liver injury with impairment of hepatocyte proliferation after two weeks of CDE diet. Additionally, we performed genetic fate tracing in mice by utilizing adeno‐associated virus serotype 8 carrying thyroid binding globulin‐driven Cre (AAV8‐TBG‐Cre) to simultaneously delete β‐catenin and permanently label hepatocytes with EYFP (KO2 mice). Importantly, in this model BECs contain β‐catenin and do not express EYFP. After 2 weeks of CDE diet, KO2 mice displayed increased liver injury, ductular reaction, fibrosis, inflammation, and a lack of hepatocyte proliferation. Finally, in KO2 mice allowed 2 weeks of recovery on normal diet after CDE diet we detected clusters of hepatocytes which expressed β‐catenin and did not express EYFP, indicating biliary origin. We did not observe expansion of EYFP‐negative hepatocytes in control mice with β‐catenin‐positive hepatocytes. To test the long‐term viability of these β‐catenin‐positive hepatocytes, KO2 mice were allowed to recover on normal diet for up to 6 months after CDE diet. Surprisingly, KO2 mice showed sustained fibrosis, inflammation, and a continued ductular reaction even after 3 months of recovery on normal diet, although this fibrosis resolved by 6 months of recovery. The resolution of fibrosis correlated with the expansion of β‐catenin‐positive hepatocytes: after 3 months of recovery hepatic Ctnnb1 expression was approximately 50% of WT2 levels, while by 6 months Ctnnb1 expression was approaching WT2 levels in KO2 mice. These results suggest that endogenous β‐catenin‐negative hepatocytes are less efficient at promoting resolution of fibrosis than β‐catenin‐positive hepatocytes. Overall, our study supports the hypothesis that BEC‐to‐hepatocyte differentiation can give rise to hepatocytes when hepatocyte proliferation is impaired. Lastly, β‐catenin in BEC‐derived hepatocyte infers a more robust cell that contributes to improved hepatic health.