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p75 neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis

p75 neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis
p75 neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis
Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. We show that human hepatic myofibroblasts co-express p75(NTR) (p75 neurotrophin receptor) and sortilin, thus facilitating differential responses to mature and pro nerve growth factor (proNGF). Although mature NGF is proapoptotic, proNGF protects human hepatic myofibroblasts from apoptosis. Moreover, in recovery from experimental liver fibrosis, the decrease in proNGF parallels loss of hepatic myofibroblasts by apoptosis. Macrophage-derived matrix metalloproteinase 7 (MMP7) cleaves proNGF in a concentration-dependent manner, and its expression in the liver coincides with falling proNGF levels. To define the dominant effect of p75(NTR)-mediated events in experimental liver fibrosis, we have used a mouse lacking the p75(NTR) ligand-binding domain but expressing the intracellular domain. We show that absence of p75(NTR) ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75(NTR) limits hepatocyte and oval cell proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Conclusion: NGF species have a differential effect on hepatic myofibroblast survival. Our data suggest that cleavage of proNGF by MMP7 during the early phase of recovery from liver fibrosis alters the pro/mature NGF balance to facilitate hepatic myofibroblast loss. Whereas fibrosis develops in the absence of p75(NTR) signaling, the dominant effects of loss of p75(NTR) ligand-mediated events are the retardation of liver fibrosis resolution via regulation of hepatic myofibroblast proliferation and apoptosis, and the reduction of hepatocyte and oval cell proliferation.
0270-9139
901-910
Kendall, Timothy J.
9417bf7e-408d-469a-9604-28e333f9adbf
Hennedige, Selina
6df7b124-3e4c-4347-9690-b8f923c74a68
Aucott, Rebecca L.
4fa5ea6f-2cd8-4d6f-813c-abdf11155aa1
Hartland, Stephen N.
ff4792ac-edcf-4cd5-acfa-4c233e5cf6b0
Vernon, Madeleine A.
882ee637-336d-4d1b-b48b-39fdc21915f3
Benyon, R. Christopher
6efa9278-56e6-47ec-9854-78afd98dd4c9
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2
Kendall, Timothy J.
9417bf7e-408d-469a-9604-28e333f9adbf
Hennedige, Selina
6df7b124-3e4c-4347-9690-b8f923c74a68
Aucott, Rebecca L.
4fa5ea6f-2cd8-4d6f-813c-abdf11155aa1
Hartland, Stephen N.
ff4792ac-edcf-4cd5-acfa-4c233e5cf6b0
Vernon, Madeleine A.
882ee637-336d-4d1b-b48b-39fdc21915f3
Benyon, R. Christopher
6efa9278-56e6-47ec-9854-78afd98dd4c9
Iredale, John P.
607673ce-77b2-4418-b317-2aa778110ee2

Kendall, Timothy J., Hennedige, Selina, Aucott, Rebecca L., Hartland, Stephen N., Vernon, Madeleine A., Benyon, R. Christopher and Iredale, John P. (2009) p75 neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis. Hepatology, 49 (3), 901-910. (doi:10.1002/hep.22701). (PMID:19072833)

Record type: Article

Abstract

Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. We show that human hepatic myofibroblasts co-express p75(NTR) (p75 neurotrophin receptor) and sortilin, thus facilitating differential responses to mature and pro nerve growth factor (proNGF). Although mature NGF is proapoptotic, proNGF protects human hepatic myofibroblasts from apoptosis. Moreover, in recovery from experimental liver fibrosis, the decrease in proNGF parallels loss of hepatic myofibroblasts by apoptosis. Macrophage-derived matrix metalloproteinase 7 (MMP7) cleaves proNGF in a concentration-dependent manner, and its expression in the liver coincides with falling proNGF levels. To define the dominant effect of p75(NTR)-mediated events in experimental liver fibrosis, we have used a mouse lacking the p75(NTR) ligand-binding domain but expressing the intracellular domain. We show that absence of p75(NTR) ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75(NTR) limits hepatocyte and oval cell proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Conclusion: NGF species have a differential effect on hepatic myofibroblast survival. Our data suggest that cleavage of proNGF by MMP7 during the early phase of recovery from liver fibrosis alters the pro/mature NGF balance to facilitate hepatic myofibroblast loss. Whereas fibrosis develops in the absence of p75(NTR) signaling, the dominant effects of loss of p75(NTR) ligand-mediated events are the retardation of liver fibrosis resolution via regulation of hepatic myofibroblast proliferation and apoptosis, and the reduction of hepatocyte and oval cell proliferation.

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Published date: March 2009

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Local EPrints ID: 70843
URI: http://eprints.soton.ac.uk/id/eprint/70843
ISSN: 0270-9139
PURE UUID: 71b3f3f5-dfc2-4748-bf0a-9afbdda9f408

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Date deposited: 09 Feb 2010
Last modified: 13 Mar 2024 20:07

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Contributors

Author: Timothy J. Kendall
Author: Selina Hennedige
Author: Rebecca L. Aucott
Author: Stephen N. Hartland
Author: Madeleine A. Vernon
Author: R. Christopher Benyon
Author: John P. Iredale

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