The role of Foxl1 in the differentiation of hepatocytes and cholangiocytes

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DESCRIPTION (provided by applicant): Chronic liver disease and cirrhosis are common disease-related causes of death in the United States. Over 2.7 million people were chronically infected with the hepatitis C virus and 1.4 million people were infected with the hepatitis B virus in 2010, according to recent CDC records. Although recent progress has been made in treating liver fibrosis and cirrhosis caused by the hepatitis C virus, liver transplantation remains the mos successful treatment for end-stage liver disease. During human liver regeneration, adult progenitor cells, known as hepatic progenitor cells (HPCs) or oval cells arise only with chronic liver injury to replenish cholangiocytes and hepatocytes. Foxl1 is one of the few proteins known to be expressed specifically by HPCs in mouse models of chronic liver injury. However, aside from belonging to the winged helix transcription factor family, little is known about the role of Foxl1 during liver regeneration. The proposed research aims to determine the role of Foxl1 in the differentiation of epithelial cells into functional hepatocytes and cholangiocytes. The goal of the first aim is to determine at what point during hepatic progenitor cell differentiation Foxl1 is necessary for hepatocyte and cholangiocyte formation. HPCs will be isolated from mice deficient in Foxl1 and carefully characterized for their ability to differentiate into functional hepatocytes. Once defects in differentiation are identified, differential gene expression will be analyzed at those time points to identify hepatocyte differentiation pathways controlled by Foxl1. In the second aim, the Foxl1-lineage from the gallbladder epithelium, the closest developmentally related tissue to the liver, would be isolated and tested for the potential to trans-differentiate into functional hepatocytes and cholangiocytes. Gallbladder epithelial cells have been reported to contain progenitor cells that can trans-differentiate into hepatocyte and cholangiocytes, but the specific progenitor population has not been clearly identified. These results will enhance our understanding of the biology of hepatic progenitor cells, specifically the molecular pathways involved in their differentiation. Ultimately, the knowledge gained by these studies will have a wide-ranging impact on the development of treatments for early and mid-stage liver disease.