Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR.
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.
Passino
Melissa A
MA
Department of Pharmacology, University of California, San Diego (UCSD), La Jolla, CA 92093-0636, USA.
Adams
Ryan A
RA
Sikorski
Shoana L
SL
Akassoglou
Katerina
K
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology*; D008099:Liver / Q000166:cytology* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration; D051379:Mice; D020932:Nerve Growth Factor / Q000494:pharmacology; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D017228:Hepatocyte Growth Factor; D020932:Nerve Growth Factor; D020741:rho GTP-Binding Proteins