Journal
HEPATOLOGY
Volume 37, Issue 1, Pages 107-117Publisher
W B SAUNDERS CO
DOI: 10.1053/jhep.2003.50005
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Funding
- NHLBI NIH HHS [R01 HL62446-04] Funding Source: Medline
- NIDDK NIH HHS [R01 DK54687-04] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL062446] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK054687] Funding Source: NIH RePORTER
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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, pair 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 CCl4 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 CCl4 injury.
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