Inside-out construction of the biliary system

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Project Summary The intrahepatic biliary tree functions to drain bile from hepatocytic canaliculi away from the liver. Congenital or acquired abnormalities in the formation and patency of intrahepatic bile ducts have severe, often fatal consequences. In the developing liver, biliary morphogenesis is a self-organizing process whereby bipotential hepatoblasts simultaneously adopt a biliary fate and organize into a continuous tubular network without cell division. Mounting evidence suggests that transdifferentiation of mature hepatocytes can also yield both normal regenerative biliary morphogenesis and abnormal disease-associated biliary `ductal reactions' in the adult liver. The mechanisms by which biliary architecture and fate are coordinated to enact this dramatic morphogenetic program and build a functional biliary tree are largely unknown. Understanding the mechanistic basis of biliary morphogenesis is necessary to harness the regenerative potential of the liver while avoiding the lethal consequences of chronic and malignant liver disease. We recently discovered that de novo lumen formation and expansion initiates biliary morphogenesis and is central to the coordination of biliary architecture and fate. Our published and preliminary studies suggest a model wherein lumen formation creates a physical signaling niche that feeds back to reinforce both biliary architecture and fate, thereby creating the biliary system from the inside out. The long-term goal of this project is to understand how lumen formation and extension guides the formation of the biliary tubular network. The successful completion of this work will address a key gap in our understanding of how to safely build this critical organ, and limit or repair it in disease.