title: Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells.
abstract: OBJECTIVE
  Factors released during liver injury, such as platelet derived growth factor-BB (PDGF), promote accumulation of myofibroblastic hepatic stellate cells (MFB) that drive the pathogenesis of cirrhosis. The hedgehog (Hh) pathway regulates remodeling of other injured tissues. This study evaluates the hypothesis that autocrine production of Sonic hedgehog (Shh) promotes MFB growth.
  
  
  METHODS
  Primary rat hepatic stellate cells (HSC) were treated without or with PDGF, a pharmacologic inhibitor of PDGF-regulated kinases, adenovirus expressing activated or dominant negative AKT, or Hh signaling inhibitors. Shh production, expression of Hh inhibitors and target genes, and HSC growth were assessed.
  
  
  RESULTS
  HSC expressed Shh, Hh pathway components, and the Hh inhibitor, Hip. During culture Hip expression fell, Shh production increased, and Hh target gene expression was induced. Neutralizing Shh antibodies promoted apoptosis. Adding PDGF increased Shh expression and MFB growth. Both processes followed activation of AKT and were abrogated by AKT inhibitors. Adenoviral delivery of activated AKT up-regulated Shh expression, demonstrating a direct role for AKT in regulating Shh expression. Shh-neutralizing antibodies and other Hh pathway inhibitors blocked the mitogenic effects of PDGF.
  
  
  CONCLUSIONS
  These results identify Shh as an autocrine growth factor for MFB and suggest a role for Hh signaling in the pathogenesis of cirrhosis.
authors.affiliation: Gastroenterology and Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Mao
authors.forename: Susanne
authors.initials: S
authors.lastname: Fleig
authors.forename: Alessia
authors.initials: A
authors.lastname: Omenetti
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Brown
authors.forename: Jason K
authors.initials: JK
authors.lastname: Sicklick
authors.forename: Yin-Xiong
authors.initials: YX
authors.lastname: Li
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000963:Antimetabolites; D019898:Autocrine Communication / Q000502:physiology*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D053148:Caspase 3 / Q000096:biosynthesis; D053179:Caspase 7 / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D005347:Fibroblasts / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics*; D022781:Hepatocytes / Q000473:pathology*; D008024:Ligands; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000502:physiology; D020286:Pericytes / Q000187:drug effects / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D000963:Antimetabolites; D053823:Hedgehog Proteins; D008024:Ligands; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D051058:Oncogene Protein v-akt; D053148:Caspase 3; D053179:Caspase 7; D001973:Bromodeoxyuridine