Foxf1 +/- mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury

Hepatology. 2003 Jan;37(1):107-17. doi: 10.1053/jhep.2003.50005.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / genetics
  • Animals
  • Apoptosis
  • Carbon Tetrachloride
  • Chemical and Drug Induced Liver Injury
  • Chemokine CXCL10
  • Chemokines, CXC / genetics
  • Collagen Type I / genetics
  • Forkhead Transcription Factors
  • Liver / cytology*
  • Liver / physiology*
  • Liver Diseases / pathology
  • Liver Diseases / physiopathology*
  • Liver Regeneration / physiology*
  • Mesoderm / cytology
  • Mice
  • Mice, Mutant Strains
  • RNA, Messenger / analysis
  • Receptor, Notch2
  • Receptors, Cell Surface / genetics
  • Transcription Factors / genetics*


  • Actins
  • Chemokine CXCL10
  • Chemokines, CXC
  • Collagen Type I
  • Forkhead Transcription Factors
  • Foxf1 protein, mouse
  • Notch2 protein, mouse
  • RNA, Messenger
  • Receptor, Notch2
  • Receptors, Cell Surface
  • Transcription Factors
  • Carbon Tetrachloride