HEPATIC STELLATE CELL-SPECIFIC PLATELET-DERIVED GROWTH FACTOR RECEPTOR α LOSS REDUCES FIBROSIS AND PROMOTES REPAIR FOLLOWING HEPATOCELLULAR INJURY

Abstract Platelet-derived growth factor receptor α (PDGFRα) plays roles in cell survival, proliferation, and differentiation, however its function in chronic liver injury sequelae like fibrosis is unknown. Hepatic stellate cells (HSCs), the primary mediators of fibrosis, undergo activation, which entails differentiation to myofibroblasts, proliferation, migration and collagen deposition, partially in response to PDGFs. To examine the role of PDGFRα in HSCs, we bred lecithin retinol acyltransferase (Lrat)-Cre recombinase and Pdgfra-floxed mice to generate Lrat-Cre Pdgfra-/- (KO) animals which were subjected to chronic liver injury through carbon tetrachloride (CCl4) treatment, bile duct ligation (BDL), and 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). While no major difference was observed after BDL or DDC, PDGFRα loss in HSCs led to a significant albeit transient reduction in fibrosis after CCl4 injury, associated with increased HSC death and reduced migration. There was continued alleviation of hepatocellular injury in KO despite ongoing CCl4 insult, associated with increased numbers of CD68 and F480 macrophages, leading to increased clearance of damaged hepatocytes. Altogether, our findings support a pro-fibrotic role of PDGFRα in HSCs during chronic liver injury in vivo via regulation of HSC survival and migration, and impact on immune microenvironment especially macrophages in clearing dying hepatocytes. Thus, our study provides pre-clinical foundation for the future testing of therapeutic PDGFRα inhibition in hepatic fibrosis, especially in combination with other therapies.