title: Basement membrane-like matrix inhibits proliferation and collagen synthesis by activated rat hepatic stellate cells: evidence for matrix-dependent deactivation of stellate cells.
abstract: During liver fibrosis hepatic stellate cells become activated, transforming into proliferative myofibroblastic cells expressing type I collagen and alpha-smooth muscle actin. They become the major producers of the fibrotic neomatrix in injured liver. This study examines if activated stellate cells are a committed phenotype, or whether they can become deactivated by extracellular matrix. Stellate cells isolated from normal rat liver proliferated and expressed mRNA for activation markers, alpha-smooth muscle actin, type I procollagen and tissue inhibitor of metalloproteinases-1 following 5-7 day culture on plastic, but culture on Matrigel suppressed proliferation and mRNA expression. Activated stellate cells were recovered from plastic by trypsinisation and replated onto plastic, type I collagen films or Matrigel. Cells replated on plastic and type I collagen films proliferated and remained morphologically myofibroblastic, expressing alpha-smooth muscle actin and type I procollagen. However, activated cells replated on Matrigel showed <30% of the proliferative rate of these cells, and this was associated with reduced cellular expression of proliferating cell nuclear antigen and phosphorylation of mitogen-activated protein kinase in response to serum. Activated HSC replated on Matrigel for 3-7 days progressively reduced their expression of mRNA for type I procollagen and alpha-smooth muscle actin and both became undetectable after 7 days. We conclude that basement membrane-like matrix induces deactivation of stellate cells. Deactivation represents an important potential mechanism mediating recovery from liver fibrosis in vivo where type I collagen is removed from the liver and stellate cells might re-acquire contact with their normal basement membrane-like pericellular matrix.
authors.affiliation: Liver Research Group, University of Southampton Division of Infection, Inflammation and Repair, Southampton General Hospital, SO16 6YD, Southampton, UK.
authors.forename: Marianna D A
authors.initials: MD
authors.lastname: Gaça
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhou
authors.forename: Razao
authors.initials: R
authors.lastname: Issa
authors.forename: Kishanee
authors.initials: K
authors.lastname: Kiriella
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.forename: R Christopher
authors.initials: RC
authors.lastname: Benyon
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D002448:Cell Adhesion; D002455:Cell Division; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D024042:Collagen Type I / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D066298:In Vitro Techniques; D016023:Integrins / Q000037:antagonists & inhibitors; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D014801:Vitamin A / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D016023:Integrins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D014801:Vitamin A; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases