Parenchymal Platelet‐Derived Growth Factor Receptor Alpha Expression Is Dispensable For Hepatic Fibrosis During Chronic Liver Injury

Abstract

Platelet‐derived growth factor receptor a (PDGFRa) is a tyrosine kinase receptor with roles in cell survival, proliferation, and differentiation, and is involved in liver development, regeneration, hepatic fibrosis and cirrhosis. While myofibroblasts derived from hepatic stellate cells and portal fibroblasts are the primary mediators of fibrosis, hepatocytes contribute to disease progression through cell death, release of cytokines and growth factors to influence myofibroblast activation, and by undergoing proliferation for regeneration. However the potential expression and function of PDGFRa in hepatocytes in the setting of chronic liver injury is unclear. In this study we investigate the role of hepatocyte PDGFRα in two murine models of chronic liver injury representing toxic (carbon tetrachloride, CCl4) and cholestatic injury (bile duct ligation, BDL). We show that PDGFRa is up‐regulated in a subset of hepatocytes in murine livers following BDL as well as following chronic CCl4 administration. Next, we generated liver‐specific PDGFRα knockout (KO) mice by interbreeding PDGFRa‐floxed and FoxA3‐cre mice. We show that following 4 weeks of CCl4 treatment, PDGFRα loss in epithelial cells did not affect the development of hepatic fibrosis. Intriguingly, comparably higher levels of PDGFRa were evident in KO and controls after 4 weeks of CCl4. In addition comparable liver injury was evident in KO and controls as assessed by serum biochemistry. Our findings suggest that PDGFRα in hepatic parenchymal cells may not be playing an important role in disease pathogenesis especially at 4 weeks after CCl4. This study also suggests that PDGFRα is primarily expressed in non‐parenchymal cell populations early during chronic liver injury.