title: β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis.
abstract: OBJECTIVE
  Rapid induction of β-PDGF receptor (β-PDGFR) is a core feature of hepatic stellate cell activation, but its cellular impact in vivo is not well characterized. We explored the contribution of β-PDGFR-mediated pathway activation to hepatic stellate cell responses in liver injury, fibrogenesis, and carcinogenesis in vivo using genetic models with divergent β-PDGFR activity, and assessed its prognostic implications in human cirrhosis.
  
  
  METHODS
  The impact of either loss or constitutive activation of β-PDGFR in stellate cells on fibrosis was assessed following carbon tetrachloride (CCl4) or bile duct ligation. Hepatocarcinogenesis in fibrotic liver was tracked after a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed from isolated stellate cells that expressed or lacked β-PDGFR to determine deregulated pathways and evaluate their association with prognostic gene signatures in human cirrhosis.
  
  
  RESULTS
  Depletion of β-PDGFR in hepatic stellate cells decreased injury and fibrosis in vivo, while its auto-activation accelerated fibrosis. However, there was no difference in development of DEN-induced pre-neoplastic foci. Genomic profiling revealed ERK, AKT, and NF-κB pathways and a subset of a previously identified 186-gene prognostic signature in hepatitis C virus (HCV)-related cirrhosis as downstream of β-PDGFR in stellate cells. In the human cohort, the β-PDGFR signature was not associated with HCC development, but was significantly associated with a poorer outcome in HCV cirrhosis.
  
  
  CONCLUSIONS
  β-PDGFR is a key mediator of hepatic injury and fibrogenesis in vivo and contributes to the poor prognosis of human cirrhosis, but not by increasing HCC development.
authors: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of General, Visceral and Transplant Surgery, University Hospital Essen, Germany.
authors: Peri
authors: P
authors: Kocabayoglu
authors: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Abigale
authors: A
authors: Lade
authors: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Youngmin A
authors: YA
authors: Lee
authors: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Ana-Cristina
authors: AC
authors: Dragomir
authors: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Xiaochen
authors: X
authors: Sun
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Maria Isabel
authors: MI
authors: Fiel
authors: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Swan
authors: S
authors: Thung
authors: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Costica
authors: C
authors: Aloman
authors: Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Philippe
authors: P
authors: Soriano
authors: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Yujin
authors: Y
authors: Hoshida
authors: Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: scott.friedman@mssm.edu.
authors: Scott L
authors: SL
authors: Friedman
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis*; D015398:Signal Transduction
chemical_list: D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Cirrhosis; Gene expression signatures; HCC; Pathway analysis; Receptor tyrosine kinase