The role of nerve growth factor and p75 neurotrophin receptor in recovery from liver fibrosis

Description/Abstract

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.