| Although the p75 neurotrophin receptor (p75NTR) has been primarily studied as a regulator of cell survival and apoptosis in the nervous system, p75NTR also exhibits widespread expression in non-neuronal tissues which can be upregulated after tissue injury. However, the biological significance of injury-induced, non-neuronal expression of p75NTR remains enigmatic. In human fibrotic and cirrhotic liver disease, p75 NTR is upregulated exclusively by hepatic stellate cells (HSCs), liver cells with neuroendocrine characteristics that can differentiate to activated matrix-producing myofibroblasts after liver injury. The work performed for my dissertation studies has led to the discovery of a novel function for p75 NTR in the regulation of HSC differentiation which can support a repair-promoting crosstalk between HSCs and hepatocytes after liver injury. In the plg-/- mouse model of liver injury, loss of p75NTR resulted in exacerbated liver pathology and inhibited HSC activation in vivo. In vitro, p75NTR-/- HSCs failed to differentiate, and adenoviral delivery of p75NTR restored activation in p75NTR-/- HSCs, suggesting that p75NTR is necessary for HSC differentiation. HSC differentiation was neurotrophin-independent, and expression of the intracellular domain of p75NTR alone was sufficient to promote HSC activation. p75NTR-/- HSCs exhibited loss of Rho activation compared to wild-type HSCs, and restoration of Rho activity completely rescued the differentiation of p75NTR-/- HSCs. Moreover, inhibition of p75NTR-mediated Rho activation prevented activation of wild-type HSCs, suggesting that p75NTR signaling through Rho promotes HSC differentiation. Additionally, we found p75 NTR-mediated HSC activation is necessary for liver repair, as the loss of p75NTR resulted in diminished liver cell proliferation in the plg-/- mouse, as well as decreased levels of hepatocyte growth factor (HGF) in the liver. In co-culture, p75NTR-/- HSCs were unable to promote hepatocyte proliferation to the extent of wild-type HSCs, but hepatocyte proliferation was recovered by addition of HGF. Overall, the results of our studies suggest that p75NTR expression and Rho activation in HSCs is necessary for their differentiation to repair-supporting, HGF-secreting cells, which in turn can promote the hepatocyte proliferation necessary for liver repair after injury or disease. |
