University of Pittsburgh

During liver regeneration, biliary epithelial cell (BEC)-driven liver regeneration occurs when hepatocyte-driven liver regeneration is not sufficient or is compromised, which is the case in chronic liver diseases. A correlation between liver progenitor cells (LPCs) and disease severity in patients with chronic liver diseases suggest that BEC­driven liver regeneration can be initiated, but activated LPCs fail to efficiently differentiate into hepatocytes in the patients. Promoting LPC differentiation into hepatocytes could recover injured liver by generating more functional hepatocytes and reducing the number of LPCs that contribute to fibrosis via secreting pro-inflammatory factors. Despite this significance, the molecular basis of LPC differentiation into functional hepatocytes remains unclear.

We have established zebrafish chronic liver injury models, in which hepatocyte-specific overexpression of oncogenes leads to LPC-mediated liver repair. Hepatocyte damage, LPC activation, fibrosis, and LPC differentiation into hepatocytes sequentially occurr in oncogene-expressing transgenic zebrafish, similarly observed in mammalian chronic liver injury models. These zebrafish models have a great potential to reveal the molecular mechanisms underlying LPC-driven liver regeneration and to identify compounds that can promote LPC differentiation into hepatocytes. Using the zebrafish models, we aim to delineate the detailed steps of LPC-driven liver regeneration. Such elucidation will enable investigation of the roles of genes and pathways in LPC-driven liver regeneration and will provide a framework to test the effects of various molecules on LPC differentiation.

Additionally, we observed liver inflammation and fibrosis in the zebrafish chronic liver injury models. Liver fibrosis is a process of wound-healing responses upon liver damages and arises a major human health problem. Although the pathogenesis of liver fibrosis is well studied, effective anti-fibrotic therapies are still lacking. In order to elucidate the molecular mechanisms underlying the progression and resolution of liver fibrosis and to develop novel and effective anti-fibrotic therapies, we will perform a chemical screen using the zebrafish liver fibrosis model. This screening will allow for understanding the molecular mechanisms underlying liver fibrosis and identifying novel targets for effective anti-fibrotic therapies.