Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
Department of Burns and Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, Shandong, China.
Exp Cell Res. 2019 Oct 1;383(1):111504. doi: 10.1016/j.yexcr.2019.111504. Epub 2019 Jul 17.
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 (p75). Using NIH/3T3 fibroblast cell lines, we examined the induction of myofibroblast differentiation stimulated by NGF. Our findings showed that p75 was in keeping with the expression of α-SMA. Herein, we investigated the role of p75 in NGF-induced myofibroblast differentiation and collagen synthesis in these cells using lentivirus transfection to overexpress and knock down. Our results showed that p75 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 p75, 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 p75 regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A. Regulation of NGF-p75 interactions represents a promising therapy for fibrotic disorders.
肌成纤维细胞的特征是重新表达α-平滑肌肌动蛋白（α-SMA），并在组织修复和重塑中发挥关键作用。除了 TGF-β1，最近的研究表明神经生长因子（NGF）对肌成纤维细胞分化和胶原合成有影响。然而，调节机制仍不清楚。NGF 效应是通过神经生长因子营养的原肌球蛋白受体激酶 A（TrkA）和 p75 神经生长因子受体（p75）的特异性表达来介导的。我们使用 NIH/3T3 成纤维细胞系，研究了 NGF 刺激的肌成纤维细胞分化的诱导。我们的研究结果表明，p75 与α-SMA 的表达一致。在此，我们使用慢病毒转染过表达和敲低，研究了 p75 在这些细胞中 NGF 诱导的肌成纤维细胞分化和胶原合成中的作用。我们的结果表明，p75 优先表达，并足以诱导肌动蛋白细胞骨架重塑，这是 NGF 诱导α-SMA 表达所必需的。此外，NGF 诱导 MRTF-A 的核易位，这一效应受 p75 调节，并且是肌成纤维细胞中α-SMA 和胶原-I 表达所必需的。使用新型 MRTF-A 途径抑制剂 CCG-203971，我们进一步证明了 MRTF-A 核定位和活性在 NGF 诱导的α-SMA 表达中的必要性。总之，我们得出结论，p75 通过 MRTF-A 调节 NGF 诱导的肌成纤维细胞分化和胶原合成。调节 NGF-p75 相互作用代表了治疗纤维化疾病的一种有前途的方法。
