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Nerve Growth Factor (NGF) modulates in vitro induced myofibroblasts by highlighting a differential protein signature.

ABSTRACT: We previously described the profibrogenic effect of NGF on conjunctival Fibroblasts (FBs) and its ability to trigger apoptosis in TGF?1-induced myofibroblasts (myoFBs). Herein, cell apoptosis/signalling, cytokines' signature in conditioned media and inflammatory as well as angiogenic pathway were investigated. Experimental myoFBs were exposed to NGF (0.1-100 ng/mL), at defined time-point for confocal and biomolecular analysis. Cells were analysed for apoptotic and cell signalling activation in cell extracts and for some inflammatory and proinflammatory/angiogenic factors' activations. NGF triggered cJun overexpression and phospho-p65-NFkB nuclear translocation. A decreased Bcl2:Bax ratio and a significant expression of smad7 were confirmed in early AnnexinV-positive myoFBs. A specific protein signature characterised the conditioned media: a dose dependent decrease occurred for IL8, IL6 while a selective increase was observed for VEGF and cyr61 (protein/mRNA). TIMP1 levels were unaffected. Herein, NGF modulation of smad7, the specific IL8 and IL6 as well as VEGF and cyr61 modulation deserve more attention as opening to alternative approaches to counteract fibrosis.

SUBMITTER: Esposito G

PROVIDER: S-EPMC7814037 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Nerve Growth Factor (NGF) modulates in vitro induced myofibroblasts by highlighting a differential protein signature.

Esposito Graziana G Balzamino Bijorn Omar BO Stigliano Egidio E Biamonte Filippo F Urbani Andrea A Micera Alessandra A

Scientific reports 20210118 1

We previously described the profibrogenic effect of NGF on conjunctival Fibroblasts (FBs) and its ability to trigger apoptosis in TGFβ1-induced myofibroblasts (myoFBs). Herein, cell apoptosis/signalling, cytokines' signature in conditioned media and inflammatory as well as angiogenic pathway were investigated. Experimental myoFBs were exposed to NGF (0.1-100 ng/mL), at defined time-point for confocal and biomolecular analysis. Cells were analysed for apoptotic and cell signalling activation in c ...[more]

PMID: 33462282

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Project description:In the conjunctiva, repeated or prolonged exposure to injury leads to tissue remodeling and fibrosis associated with dryness, lost of corneal transparency and defect of ocular function. At the site of injury, fibroblasts (FB) migrate and differentiate into myofibroblasts (myoFB), contributing to the healing process together with other cell types, cytokines and growth factors. While the physiological deletion of MyoFB is necessary to successfully end the healing process, myoFB prolonged survival characterizes the pathological process of fibrosis. The reason for myoFB persistence is poorly understood. Nerve Growth Factor (NGF), often increased in inflamed stromal conjunctiva, may represent an important molecule both in many inflammatory processes characterized by tissue remodeling and in promoting wound-healing and well-balanced repair in humans. NGF effects are mediated by the specific expression of the NGF neurotrophic tyrosine kinase receptor type 1 (trkA(NGFR)) and/or the pan-neurotrophin glycoprotein receptor (p75(NTR)). Therefore, a conjunctival myoFB model (TGF?1-induced myoFB) was developed and characterized for cell viability/proliferation as well as ?SMA, p75(NTR) and trkA(NGFR) expression. MyoFB were exposed to acute and chronic NGF treatment and examined for their p75(NTR)/trkA(NGFR), ?SMA/TGF?1 expression, and apoptosis. Both NGF treatments significantly increased the expression of p75(NTR), associated with a deregulation of both ?SMA/TGF?1 genes. Acute and chronic NGF exposures induced apoptosis in p75(NTR) expressing myoFB, an effect counteracted by the specific trkA(NGFR) and/or p75(NTR) inhibitors. Focused single p75(NTR) and double trkA(NGFR)/p75(NTR) knocking-down experiments highlighted the role of p75(NTR) in NGF-induced apoptosis. Our current data indicate that NGF is able to trigger in vitro myoFB apoptosis, mainly via p75(NTR). The trkA(NGFR)/p75(NTR) ratio in favor of p75(NTR) characterizes this process. Due to the lack of effective pharmacological agents for balanced tissue repairs, these new findings suggest that NGF might be a suitable therapeutic tool in conditions with impaired tissue healing.

Dataset Information

Nerve Growth Factor (NGF) modulates in vitro induced myofibroblasts by highlighting a differential protein signature.

Publications

Nerve Growth Factor (NGF) modulates in vitro induced myofibroblasts by highlighting a differential protein signature.

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