Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury.
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.
Kalinichenko
Vladimir V
VV
Department of Molecular Genetics, College of Medicine, University of Illinois at Chicago, 60607, USA.
Bhattacharyya
Dibyendu
D
Zhou
Yan
Y
Gusarova
Galina A
GA
Kim
Wooram
W
Shin
Brian
B
Costa
Robert H
RH
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*
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