Rodent hepatic myofibroblasts are susceptible to nerve growth factor-mediated apoptosis through p75 neurotrophin receptor ligation. Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. I show that human hepatic myofibroblasts exhibit differential responses to mature and pro-nerve growth factor/p75 neurotrophin receptor-mediated signals. Whilst mature nerve growth factor is proapoptotic, pronerve growth factor protects human hepatic myofibroblasts from serum-deprivation and cycloheximide-induced apoptosis. To define the dominant effect of p75 neurotrophin receptor-mediated events in experimental liver fibrosis I have used a mouse lacking the p75 neurotrophin receptor ligand-binding domain but expressing the intracellular domain. I show that absence of p75 neurotrophin receptor ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75 neurotrophin receptor limits hepatocyte proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Moreover, in recovery from experimental liver fibrosis the fall in pro-nerve growth factor mirrors loss of hepatic myofibroblasts by apoptosis. Thus, nerve growth factor species have a differential effect on hepatic myofibroblast survival, and p75 neurotrophin receptor ligand-mediated events facilitate reduction of liver fibrosis via regulation of hepatic myofibroblast proliferation and apoptosis, and hepatocyte proliferation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:494721 |
| Date | January 2008 |
| Creators | Kendall, Timothy James |
| Contributors | Iredale, John ; Benyon, Chris |
| Publisher | University of Southampton |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://eprints.soton.ac.uk/161479/ |
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