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American Liver Foundation
39 Broadway, Suite 2700
New York, New York 10006
Alexander M. White, III Postdoctoral Research Fellowship
Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
Epithelial-To-Mesenchymal Transition in Biliary Fibrosis
Disorders of the biliary tract comprise a small but significant portion of the overall pediatric disease burden. Many of these pathologies lead to hepatic fibrosis and the need for liver transplantation. Most prominent is biliary atresia (BA), a rapidly progressive fibroinflammatory disorder that destroys the biliary tree in neonates. It is the leading indication for pediatric liver transplantation and has no effective treatment. Recent studies from Dr. Chu’s lab and others suggest that epithelial-to-mesenchymal transition (EMT), a process by which epithelial cells change into fibrogenic myofibroblasts, contributes to biliary fibrosis.
Dr. Chu’s hypothesis is that epithelial dysfunction plays a significant role in generating fibrosis in BA. This may be complete EMT, or a partial EMT in which epithelial cells express some mesenchymal markers. The overall goal of this project is to determine the mechanisms of this EMT-like process in BA and other diseases resulting in biliary fibrosis. There are two Specific Aims. Aim 1 focuses on the determining the role of biliary EMT in vivo through lineage tracing. Starting with a transgenic murine strain designed to permanently label cells of hepatobiliary origin, Dr. Chu’s team is using several disease models including bile duct ligation to attempt to show that cells undergoing a full or partial EMT and contributing to biliary fibrosis originate from biliary epithelial cells (BECs). Dr. Chu believes that he and his team will demonstrate either that EMT generates a significant number of fibrogenic cells in the setting of biliary fibrosis, or that biliary epithelial cells with mesenchymal characteristics play a significant role in the emergence of other fibrogenic cells. Aim 2 is to determine the role of mechanical forces in TGF-β-mediated biliary EMT/partial EMT. Specifically, in Aim 2A, using matrix-coated polyacrylamide gels of variable stiffness, he and his team are examining the in vitro effects of matrix stiffness on the ability of BECs to undergo EMT, while in Aim 2B, Dr. Chu and his team are studying how derangements of biliary cilia, which act as critical environmental and mechanotransductive sensors, may influence the ability of BECs to undergo EMT. His lab has preliminary data showing that matrix stiffness is a determining factor in progression to EMT in BECs in vitro. He also found that BEC cilia are severely deranged in BA and that deciliation may promote EMT in BECs that are exposed to TGF-β1.
Dr. Chu’s findings could establish EMT, or a partial EMT, as a key participant in biliary fibrosis and could describe novel mechanisms by which mechanical forces may influence epithelial cell fate and contribute to fibrosis. Ultimately, by exposing EMT mechanisms and thereby uncovering potential therapeutic targets, he hopes to improve the lives of patients with BA and other biliary diseases.