title: Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury.
abstract: Previous studies have shown that haploinsufficiency of the splanchnic and septum transversum mesoderm Forkhead Box (Fox) f1 transcriptional factor caused defects in lung and gallbladder development and that Foxf1 heterozygous (+/-) mice exhibited defective lung repair in response to injury. In this study, we show that Foxf1 is expressed in hepatic stellate cells in developing and adult liver, suggesting that a subset of stellate cells originates from septum transversum mesenchyme during mouse embryonic development. Because liver regeneration requires a transient differentiation of stellate cells into myofibroblasts, which secrete type I collagen into the extracellular matrix, we examined Foxf1 +/- liver repair following carbon tetrachloride injury, a known model for stellate cell activation. We found that regenerating Foxf1 +/- liver exhibited defective stellate cell activation following CCl(4) liver injury, which was associated with diminished induction of type I collagen, alpha-smooth muscle actin, and Notch-2 protein and resulted in severe hepatic apoptosis despite normal cellular proliferation rates. Furthermore, regenerating Foxf1 +/- livers exhibited decreased levels of interferon-inducible protein 10 (IP-10), delayed induction of monocyte chemoattractant protein 1 (MCP-1) levels, and aberrantly elevated expression of transforming growth factor beta1. In conclusion, Foxf1 +/- mice exhibited abnormal liver repair, diminished activation of hepatic stellate cells, and increased pericentral hepatic apoptosis following CCl(4) injury.
authors.affiliation: Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, 60607, USA.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kalinichenko
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Bhattacharyya
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Galina A
authors.initials: GA
authors.lastname: Gusarova
authors.forename: Wooram
authors.initials: W
authors.lastname: Kim
authors.forename: Brian
authors.initials: B
authors.lastname: Shin
authors.forename: Robert H
authors.initials: RH
authors.lastname: Costa
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D051858:Forkhead Transcription Factors; D008099:Liver / Q000166:cytology* / Q000502:physiology*; D008107:Liver Diseases / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration / Q000502:physiology*; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000032:analysis; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000199:Actins; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D024042:Collagen Type I; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; C497765:Notch2 protein, mouse; D012333:RNA, Messenger; D051883:Receptor, Notch2; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D002251:Carbon Tetrachloride