University of Pittsburgh

During regeneration, hepatocytes can be derived from either preexisting hepatocytes or biliary epithelial cells (BECs). When hepatocyte-driven liver regeneration is compromised, which is the case in chronic liver diseases, BEC-driven liver regeneration takes place. Understanding the molecular mechanisms of this BEC-driven liver regeneration should provide significant insights into how to promote innate liver regeneration in patients with severe liver diseases as therapeutics. We have established several innovative zebrafish liver regeneration models in which BECs extensively give rise to hepatocytes. Using these models, we have taken several approaches to better understand the mechanisms of BEC-driven liver regeneration, including chemical screening and RNAseq analyses. Currently, we investigate how (1) epigenetic factors, (2) metabolism, and (3) FGFR signaling regulate BEC-driven liver regeneration.

Upon severe biliary damage, hepatocytes transdifferentiate into BECs, similar to BEC conversion to hepatocytes in the settings of severe hepatocyte damage. We recently developed two zebrafish models for hepatocyte-to-BEC transdifferentiation. Using these models, we investigate the molecular mechanisms underlying this plasticity.