title: Gene expression profiling of early hepatic stellate cell activation reveals a role for Igfbp3 in cell migration.
abstract: BACKGROUND
  Scarring of the liver is the result of prolonged exposure to exogenous or endogenous stimuli. At the onset of fibrosis, quiescent hepatic stellate cells (HSCs) activate and transdifferentiate into matrix producing, myofibroblast-like cells.
  
  
  OBJECTIVE
  To identify key players during early HSC activation, gene expression profiling was performed on primary mouse HSCs cultured for 4, 16 and 64 hours. Since valproic acid (VPA) can partly inhibit HSC activation, we included VPA-treated cells in the profiling experiments to facilitate this search.
  
  
  RESULTS
  Gene expression profiling confirmed early changes for known genes related to HSC activation such as alpha smooth muscle actin (Acta2), lysyl oxidase (Lox) and collagen, type I, alpha 1 (Col1a1). In addition we noticed that, although genes which are related to fibrosis change between 4 and 16 hours in culture, most gene expression changes occur between 16 and 64 hours. Insulin-like growth factor binding protein 3 (Igfbp3) was identified as a gene strongly affected by VPA treatment. During normal HSC activation Igfbp3 is up regulated and this can thus be prevented by VPA treatment in vitro and in vivo. siRNA-mediated silencing of Igfbp3 in primary mouse HSCs induced matrix metalloproteinase (Mmp) 9 mRNA expression and strongly reduced cell migration. The reduced cell migration after Igfbp3 knock-down could be overcome by tissue inhibitor of metalloproteinase (TIMP) 1 treatment.
  
  
  CONCLUSIONS
  Igfbp3 is a marker for culture-activated HSCs and plays a role in HSC migration. VPA treatment prevents Igfbp3 transcription during activation of HSCs in vitro and in vivo.
authors.affiliation: Liver Cell Biology Laboratory, Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Mannaerts
authors.affiliation: Liver Cell Biology Laboratory, Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Ben
authors.initials: B
authors.lastname: Schroyen
authors.affiliation: Liver Cell Biology Laboratory, Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Stefaan
authors.initials: S
authors.lastname: Verhulst
authors.affiliation: Department of Cellular and Molecular Medicine, Leuven, Belgium.
authors.forename: Leentje
authors.initials: L
authors.lastname: Van Lommel
authors.affiliation: Department of Cellular and Molecular Medicine, Leuven, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.affiliation: Department of Biostatistics and Medical Informatics, Faculty of Medicine and Pharmacy,Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Nyssen
authors.affiliation: Liver Cell Biology Laboratory, Vrije Universiteit Brussel, Brussel, Belgium.
authors.forename: Leo A
authors.initials: LA
authors.lastname: van Grunsven
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D059467:Transcriptome; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D014635:Valproic Acid