Regulation of Hepatic Stellate Cell Differentiation by the Neurotrophin Receptor p75 ^NTR

Abstract

Differentiation of hepatic stellate cells (HSCs) to extracellular matrix- and growth factor-producing cells supports liver regeneration through promotion of hepatocyte proliferation. We show that the neurotrophin receptor p75NTR, a tumor necrosis factor receptor superfamily member expressed in HSCs after fibrotic and cirrhotic liver injury in humans, is a regulator of liver repair. In mice, depletion of p75NTR exacerbated liver pathology and inhibited hepatocyte proliferation in vivo. p75NTR-/- HSCs failed to differentiate to myofibroblasts and did not support hepatocyte proliferation. Moreover, inhibition of p75NTR signaling to the small guanosine triphosphatase Rho resulted in impaired HSC differentiation. Our results identify signaling from p75NTR to Rho as a mechanism for the regulation of HSC differentiation to regeneration-promoting cells that support hepatocyte proliferation in the diseased liver.

Nuclear factor-κB and the hepatic inflammation-fibrosis-cancer axis

“…42 A recent paper in Science highlighted the importance of activated HMs in hepatocyte proliferation. 43 The persistence and inflammatory/mitogenic phenotype of HMs inclusive of their expression of IL-6 and MMP9 depends on a high constitutive NF-B activity that is regulated at least in part by transcriptional repression of I B-␣ (mediated by CBF-1 and MeCP2) but also by IKK-dependent mechanisms under investigation in our laboratory. 44,45 Suppression of IKK activity in HMs with either a cell-permeable peptide that blocks the interaction of IKK␣/␤ with NEMO or by treatment with sulfasalazine (which inhibits IKK␣/␤) promotes Jun Nterminal kinase-dependent apoptosis.…”

Thyroid hormones induce activation of rat hepatic stellate cells through increased expression of p75 neurotrophin receptor and direct activation of Rho

“…9 Recent studies have shed light on the function of p75 neurotrophin receptor (p75NTR) in HSC activation and show that in p75NTRÀ/À mice, HSC are unable to become activated and to express aSMA. 10 Interestingly, p75NTR is effective in activating HSC in the absence of its ligand, nerve growth factor (NGF), signaling through activation of guanosine triphosphatase Rho. 10 Activation of members of Rho GTPase is reported to be crucial for HSC activation, as Rho inhibition attenuates liver fibrosis in several in vivo models.…”

“…10 Interestingly, p75NTR is effective in activating HSC in the absence of its ligand, nerve growth factor (NGF), signaling through activation of guanosine triphosphatase Rho. 10 Activation of members of Rho GTPase is reported to be crucial for HSC activation, as Rho inhibition attenuates liver fibrosis in several in vivo models. 11,12 Quiescent HSC do not express p75NTR, but start expressing it on activation, 13 whereas hepatocytes do not express this receptor.…”

Epigenetic Inactivation and Tumor-Suppressor Behavior of NGFR in Human Colorectal Cancer

“…p75NGFR has different functions based on the tumor type in which it is found. For example, it has been shown to exert a tumor-promoting effect in brain tumors and melanomas (11,12), whereas it has also been proposed as a potential tumor suppressor in bladder (7), stomach (9) and liver cancers (10). However, with the exception of a previous study reporting hypermethylation of p75NGFR in the serum of patients with colorectal cancer (13), no other studies to date have reported the methylation status, expression level, or function of p75NGFR in colorectal cancer.…”

“…The expression of p75NGFR has been observed in several human cancers, such as thyroid carcinoma, stomach cancer, and liver cancer (5)(6)(7)(8)(9)(10). p75NGFR has different functions based on the tumor type in which it is found.…”