Cell-cell adhesion-mediated signaling determines epithelial polarization in the liver

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NOTE: You must submit in Word format, not PDF, for eRA to update all the systems. The liver is our largest metabolic organ. It produces proteins, lipids, clotting factors and glycogen while dispensing bile and detoxifying xenobiotics. In order to transport these different substances, a sophisticated network of liver venules, capillaries and interstitial conduits has evolved. An essential feature of this network are the lumen-forming epithelia that give rise to two major liver cell populations: (1) hepatocytes - the main parenchymal cell type, and (2) bile duct cells. Both acquire radically different polarity phenotypes adapted to their different functions (Fig.1): Bile duct cells, which form simple conduits for bile, organize like other tubular epithelia around a central lumen. Hepatocytes, by contrast form single-cell cords, aligned along blood vessels on either side and with a capillary-like luminal network (bile canaliculi) running between them. This organization facilitates their extensive bi-directional molecular exchange with the blood, while allowing bile acid excretion into the bile canaliculi. How hepatocytes obtain this unique morphological phenotype is poorly understood. Indeed, because bile canaliculi are not visible by conventional H&E tissue stain, the study of hepatocyte polarity has largely been neglected. The resulting gap in our knowledge has greatly hindered our ability to better understand the molecular basis of common liver diseases, which typically present with changes in hepatocyte polarity and morphology. It also severely limits our ongoing efforts to engineer hepatic tissue that can be used for transplantation, toxicology and gene therapy studies. To tackle these issues, we developed a unique tissue culture model in which the polarity phenotype can be switched from ductal to hepatocytic and utilized it to identify molecular mechanisms that distinguish the hepatocytic from the ductal polarization program. In parallel, we developed protocols to in vitro differentiate polarized hepatocytes from their precursors and evaluated proteins critical for the hepatocytic polarity switch in these physiological relevant systems. This led to the discovery of the dual PKA-anchoring and Rho-activating protein AKAP13 as regulator of bile canaliculi elongation. Elucidating the mechanisms underlying its function, as proposed here, will reveal a critical morphological mechanisms of hepatocyte polarization.