Hepatic Stellate Cell-Specific Platelet-Derived Growth Factor Receptor-α Loss Reduces Fibrosis and Promotes Repair after Hepatocellular Injury

Abstract

Platelet-derived growth factor receptor (PDGFR)-α plays roles in cell survival, proliferation, and differentiation; however, its function in chronic liver injury sequelae, such as 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 PDGFR-α in HSCs, Lrat-Cre recombinase and Pdgfra-floxed mice were bred to generate Lrat-CrePdgfra-/- (knockout) animals, which were subjected to chronic liver injury through carbon tetrachloride treatment, bile duct ligation, and 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Although no major difference was observed after other types of liver injury, PDGFR-α loss in HSCs led to a significant albeit transient reduction in fibrosis after carbon tetrachloride injury, associated with increased HSC death and reduced migration. There was continued alleviation of hepatocellular injury in knockout mice despite ongoing carbon tetrachloride insult, associated with increased numbers of CD68 and F480 macrophages and increased clearance of damaged hepatocytes. Altogether our findings support a profibrotic role of PDGFR-α in HSCs during chronic liver injury in vivo via regulation of HSC survival and migration and affect the immune microenvironment, especially macrophages in clearing dying hepatocytes. Thus, our study provides a preclinical foundation for the future testing of therapeutic PDGFR-α inhibition in hepatic fibrosis, especially in combination with other therapies.