title: Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury.
abstract: OBJECTIVE
  Hepatic stellate cells (HSCs) express alpha-smooth muscle actin (alphaSMA) and acquire a profibrogenic phenotype upon activation by noxious stimuli. Insulin-like growth I (IGF-I) has been shown to stimulate HSCs proliferation in vitro, but it has been reported to reduce liver damage and fibrogenesis when given to cirrhotic rats.
  
  
  METHODS
  The authors used transgenic mice (SMP8-IGF-I) expressing IGF-I under control of alphaSMA promoter to study the influence of IGF-I synthesised by activated HSCs on the recovery from liver injury.
  
  
  RESULTS
  The transgene was expressed by HSCs from SMP8-IGF-I mice upon activation in culture and in the livers of these animals after CCl4 challenge. Twenty four hours after administration of CCl4 both transgenic and wild type mice showed similar extensive necrosis and increased levels of serum transaminases. However at 72 hours SMP8-IGF-I mice exhibited lower serum transaminases, reduced hepatic expression of alphaSMA, and improved liver morphology compared with wild type littermates. Remarkably, at this time all eight CCl4 treated wild type mice manifested histological signs of liver necrosis that was severe in six of them, while six out of eight transgenic animals had virtually no necrosis. In SMP8-IGF-I mice robust DNA synthesis occurred earlier than in wild type animals and this was associated with enhanced production of HGF and lower TGFbeta1 mRNA expression in the SMP8-IGF-I group. Moreover, Colalpha1(I) mRNA abundance at 72 hours was reduced in SMP8-IGF-I mice compared with wild type controls.
  
  
  CONCLUSIONS
  Targeted overexpression of IGF-I by activated HSCs restricts their activation, attenuates fibrogenesis, and accelerates liver regeneration. These effects appear to be mediated in part by upregulation of HGF and downregulation of TGFbeta1. The data indicate that IGF-I can modulate the cytokine response to liver injury facilitating regeneration and reducing fibrosis.
authors.affiliation: Division of Hepatology and Gene Therapy, Clinica Universitaria and Medical School, Center for Applied Medical Research (CIMA), University of Navarra, 31008, Pamplona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Sanz
authors.forename: J B
authors.initials: JB
authors.lastname: Pucilowska
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: C M
authors.initials: CM
authors.lastname: Rodríguez-Ortigosa
authors.forename: P K
authors.initials: PK
authors.lastname: Lund
authors.forename: D A
authors.initials: DA
authors.lastname: Brenner
authors.forename: C R
authors.initials: CR
authors.lastname: Fuller
authors.forename: J G
authors.initials: JG
authors.lastname: Simmons
authors.forename: A
authors.initials: A
authors.lastname: Pardo
authors.forename: M-L
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.forename: J A
authors.initials: JA
authors.lastname: Fagin
authors.forename: J
authors.initials: J
authors.lastname: Prieto
mesh_terms: D000199:Actins; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1
chemical_list: D000199:Actins; D005353:Fibronectins; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007334:Insulin-Like Growth Factor I; D003094:Collagen; D002251:Carbon Tetrachloride