title: Activation of platelet-derived growth factor receptor alpha contributes to liver fibrosis.
abstract: Chronic liver injury leads to fibrosis, cirrhosis, and loss of liver function. Liver cirrhosis is the 12th leading cause of death in the United States, and it is the primary risk factor for developing liver cancer. Fibrosis and cirrhosis result from activation of hepatic stellate cells (HSCs), which are the primary collagen producing cell type in the liver. Here, we show that platelet-derived growth factor receptor α (PDGFRα) is expressed by human HSCs, and PDGFRα expression is elevated in human liver disease. Using a green fluorescent protein (GFP) reporter mouse strain, we evaluated the role of PDGFRα in liver disease in mice and found that mouse HSCs express PDGFRα and expression is upregulated during carbon tetrachloride (CCl4) induced liver injury and fibrosis injection. This fibrotic response is reduced in Pdgfrα heterozygous mice, consistent with the hypothesis that liver fibrosis requires upregulation and activation of PDGFRα. These results indicate that Pdgfrα expression is important in the fibrotic response to liver injury in humans and mice, and suggest that blocking PDGFRα-specific signaling pathways in HSCs may provide therapeutic benefit for patients with chronic liver disease.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hayes
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Department of Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Riehle
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Department of Pharmacology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Masami
authors.initials: M
authors.lastname: Shimizu-Albergine
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Renay L
authors.initials: RL
authors.lastname: Bauer
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Johansson
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Center for Cardiovascular Biology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Mahoney
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America; Department of Surgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Yeung
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
mesh_terms: D000483:Alleles; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta