Contributions of biliary epithelial cells to hepatocyte homeostasis and regeneration in zebrafish

Whether transdifferentiation of the biliary epithelial cells (BECs) to hepatocytes occurs under physiological conditions and contributes to liver homeostasis remains under long-term debate. Similar questions have been raised under pathological circumstances if a fibrotic liver is suffered from severe injuries. To address these questions in zebrafish, we established a sensitive lineage tracing system specific for the detection of BEC-derived hepatocytes. The BEC-to-hepatocyte transdifferentiation occurred and became minor contributors to hepatocyte homeostasis in a portion of adult individuals. The BEC-derived hepatocytes distributed in clusters in the liver. When a fibrotic liver underwent extreme hepatocyte damages, BEC-to-hepatocyte transdifferentiation acted as the major origin of regenerating hepatocytes. In contrast, partial hepatectomy failed to induce the BEC-to-hepatocyte conversion. In conclusion, based on a sensitive lineage tracing system, our results suggest that BECs are able to transdifferentiate into hepatocytes and contribute to both physiological hepatocyte homeostasis and pathological regeneration.