Donghun Shin, PhD*
Biomedical Science Tower Three #5063
3501 5th Avenue
Pittsburgh, PA 15260
In the Department of Development Biology, Dr. Shin and his team’s long-term goal is to contribute to a better treatment of liver failure or liver diseases by understanding the molecular and cellular mechanisms regulating liver development and regeneration using zebrafish as a vertebrate model system.
The liver is the most regenerative organ; however, this capacity is greatly reduced in the diseased liver, making liver transplantation the only definitive treatment for end-stage chronic liver diseases. The shortage of donor livers however makes this therapy extremely limited. If innate liver regeneration could be augmented in chronic liver patients, it may mitigate the diseases and improve quality of life. Thus, means to augment innate liver regeneration is considered a desirable and necessary alternative therapy. Understanding the mechanisms of liver regeneration is a prerequisite for the development of such a therapy. During liver regeneration, hepatocytes can be derived from preexisting hepatocytes or from biliary epithelial cells (BECs). BEC-driven liver regeneration occurs when hepatocyte-driven liver regeneration is compromised, which is the case in chronic liver diseases. A correlation between the number of activated BECs, oval cells, and disease severity in patients with chronic liver diseases suggest that BEC-driven liver regeneration can be initiated, but oval cells fail to differentiate into hepatocytes in the patients. Understanding the entire process of BEC-driven liver regeneration should provide significant insights into how to augment this process in liver patients as therapies.
Dr. Shin and his team have established an innovative zebrafish liver regeneration model in which BECs extensively give rise to hepatocytes, thereby leading to full liver recovery. Using this model, the team has taken several approaches to better understand the mechanisms of BEC-driven liver regeneration: 1) chemical screening, 2) RNAseq analyses, and 3) genes/pathways important for liver development. Currently, they investigate how 1) epigenetic factors, 2) Bmp signaling, and 3) inflammatory signals regulate BEC-driven liver regeneration.
In addition to the regeneration study, Dr. Shin and his team study hepatic biliary morphogenesis. Hepatocytes are a key cell type of most liver functions; BECs are a unit to make hepatic biliary ducts that drain bile from hepatocytes to the gallbladder. If the biliary ducts are not properly formed, bile is leaky, causing liver damage and eventually leading to cirrhosis. Thus, a better understanding of biliary morphogenesis could allow for faster diagnoses of biliary diseases, which is important for patients’ survival. Based on their observation that suppressing or enhancing Wnt signaling results in abnormal biliary morphogenesis, the team investigates how Wnt signaling regulates biliary morphogenesis at the cellular and molecular levels. Moreover, in collaboration with clinicians, they investigate the functions of candidate genes, identified by genome-wide association studies from biliary atresia patients, in biliary morphogenesis. This study will reveal susceptibility genes of biliary atresia, the most common indication for pediatric liver transplantation.
Dr. Shin recently received NIH R01 funding (R01DK101426), 2014-2019.
School of Medicine – Department of Developmental Biology