ELUCIDATING MECHANISMS OF LIVER DEVELOPMENT AND LIVER PROGENITOR CELL-DRIVEN REGENERATION IN ZEBRAFISH

[摘要] Chronic liver disease encompasses the steady destruction of hepatic tissue over time, resulting in the replacement of healthy liver tissue with damaged fibrotic and cirrhotic tissue. Among other symptoms, cirrhosis manifests itself with regenerative hepatic nodules and portal hypertension, triggering a loss of liver functionality and poor quality of life. Moreover, in the United States, cirrhosis remains the 12th leading cause of death, incurring healthcare costs of billions of dollars. Despite the astronomical costs and limited palliative care, the only effective treatment for cirrhosis is liver transplantation. The demand for liver transplants, however, far exceeds the availability of donor livers, underpinning the need for harnessing the liver’s innate regenerative capacity. Using zebrafish as a model organism, the main aim of this dissertation is to elucidate the underlying mechanisms of liver progenitor cell (LPC)-driven liver regeneration as well as liver development, since events involved in the former process can be recapitulated in the latter. Our lab previously characterized the biliary epithelial cell (BEC)-driven liver regeneration in which after extensive hepatocyte ablation, BECs dedifferentiate into LPCs and subsequently, the LPCs can re-differentiate into mature hepatocytes/BECs. During this regenerative process, our RNAseq analysis showed an upregulation of genes mediating the Bone Morphogenetic Protein (BMP) pathway, including a BMP downstream target gene, Inhibitor of DNA binding 2a (Id2a). Using loss- and gain-of-function approaches, we show Id2a to be an important regulator of hepatic outgrowth during liver development as well as an important mediator of BEC repopulation in LPC-driven liver regeneration. In addition, as LPC activation is often accompanied by an inflammatory cell response, our second focus was on the role of Signal Transducer and Activator of Transcription 3 (Stat3) in the LPC-driven liver regeneration model. By chemically inhibiting Stat3, we show Stat3 signaling regulates not only the differentiation of LPCs into hepatocytes, but also the proliferation of BECs during LPC-driven liver regeneration.

[发布机构] the University of Pittsburgh