p75 neurotrophin receptor regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A

• Published in: Experimental cell research 2019-10, Vol.383 (1), p.111504, Article 111504
• Main Authors: Liu, Zhenxing, Cao, Yongqian, Liu, Guijun, Yin, Siyuan, Ma, Jiaxu, Liu, Jian, Zhang, Min, Wang, Yibing
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; Animals; Apoptosis; Cell Differentiation - drug effects; Cell Movement; Cell Nucleus - metabolism; Cell Proliferation; Collagen - metabolism; Differentiation; Mice; MRTF-A; Myofibroblast; Myofibroblasts - cytology; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Nerve Growth Factor - pharmacology; NGF; NIH 3T3 Cells; p75NTR; Protein Transport; Receptor, trkA - genetics; Receptor, trkA - metabolism; Receptors, Nerve Growth Factor - genetics; Receptors, Nerve Growth Factor - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2019.111504

Myofibroblasts are characterized by de novo expression of α-smooth muscle actin (α-SMA) and play a key role in tissue repair and remodeling. In addition to TGF-β1, recent studies have shown that nerve growth factor (NGF) has effects on myofibroblast differentiation and collagen synthesis. However, the regulatory mechanism remains poorly defined. NGF effects are mediated by the specific expression of the NGF neurotrophic tropomyosin-receptor kinase A (TrkA) and p75 neurotrophin receptor (p75NTR). Using NIH/3T3 fibroblast cell lines, we examined the induction of myofibroblast differentiation stimulated by NGF. Our findings showed that p75NTR was in keeping with the expression of α-SMA. Herein, we investigated the role of p75NTR in NGF-induced myofibroblast differentiation and collagen synthesis in these cells using lentivirus transfection to overexpress and knock down. Our results showed that p75NTR was preferentially expressed and was sufficient to induce actin cytoskeleton remodeling, which was required for NGF-induced α-SMA expression. Furthermore, NGF induced nuclear translocation of MRTF-A, an effect that was regulated by p75NTR, and required for α-SMA and collagen-I expression in myofibroblasts. Using a novel MRTF-A pathway inhibitor, CCG-203971, we further demonstrated the requirement of MRTF-A nuclear localization and activity in NGF-induced α-SMA expression. In conclusion, we conclude that p75NTR regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A. Regulation of NGF-p75NTR interactions represents a promising therapy for fibrotic disorders. •NGF promotes myofibroblast differentiation in NIH/3T3 fibroblast cell lines.•The expression of p75NTR is upregulated during NGF-induced myofibroblast differentiation.•Blockage or over-expression of p75NTR affect NGF induced the synthesis of α-SMA and collagen-I.•One of the p75NTR regulation mechanismses is via actin cytoskeleton remodeling and MRTF-A nuclear translocation.