Dedifferentiation-Dependent Regeneration of the Biliary Ductal Epithelium in Response to Hepatic Injury in TFF1-Deficient Mice

The mechanisms involved in the regeneration of biliary epithelial cells (BECs) after liver injury remain unclear. In this study, we employed KRT19Cre^ERT/LSL-tdTomato (KT) mice and KT/TFF1KO mice to clarify the regeneration and cell fate of BECs via lineage tracing. Tamoxifen (TAM) was administered to the mice to label cytokeratin 19 (CK19)-positive BECs. The mice were subsequently fed a choline-deficient, ethionine-supplemented (CDE) diet for four weeks, after which the mouse livers were analyzed. Whereas the proportion of tdTomato⁺ cells in CK19-positive BECs decreased in the KT mice, it remained high in the KT/TFF1KO mice. Then, we analyzed hepatic progenitor cells (HPCs), the possible source of BECs. Although tdTomato-labeled HPCs were rarely found in the pretreatment mice, they were frequently found in the KT/TFF1KO mice after the CDE diet, suggesting the dedifferentiation of tdTomato-labeled BECs to HPCs. These results indicate not only that the loss of TFF1 accelerates the dedifferentiation of BECs into HPCs but also that HPCs are the source of BECs in TFF1KO mice. In addition, tdTomato-labeled HNF4α-positive hepatocytes were frequently found in the KT/TFF1KO mice, revealing the transdifferentiation of BECs to hepatocytes. The role of TFF1 as an inducer of biliary differentiation might be useful in the treatment of patients with hepatic or biliary dysfunction.