p75 neurotrophin receptor regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A
p75 neurotrophin receptor regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A
复制标题
p75神经营养素受体通过MRTF-A调节NGF诱导的肌成纤维细胞分化和胶原合成
DOI：
10.1016/j.yexcr.2019.111504
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发表时间：
2019-10-01
影响因子：
3.7
通讯作者：
Wang, Yibing
中科院分区：
文献类型：
--
作者：
Liu, Zhenxing;Cao, Yongqian;Wang, Yibing
肌成纤维细胞的特征在于α-平滑肌肌动蛋白（α-SMA）的从头表达，并且在组织修复和重塑中起关键作用。除了TGF-β 1，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，监管机制仍然不明确。神经生长因子的作用是由神经生长因子神经营养原肌球蛋白受体激酶A（TrkA）和p75神经营养因子受体（p75（NTR））的特异性表达介导的。使用NIH/3 T3成纤维细胞系，我们研究了NGF刺激的肌成纤维细胞分化的诱导。结果表明，p75（NTR）与α-SMA的表达一致。在此，我们研究了p75（NTR）在神经生长因子诱导的肌成纤维细胞分化和胶原合成在这些细胞中的作用，使用慢病毒转染过表达和敲低。我们的研究结果表明，p75 NTR优先表达，足以诱导肌动蛋白细胞骨架重塑，这是所需的神经生长因子诱导的α-SMA的表达。此外，NGF诱导MRTF-A的核转位，这是一种受p75（NTR）调节的效应，并且是肌成纤维细胞中α-SMA和胶原-I表达所需的。使用一种新的MRTF-A通路抑制剂CCG-203971，我们进一步证明了在NGF诱导的α-SMA表达中MRTF-A核定位和活性的要求。总之，我们得出结论，p75（NTR）调节神经生长因子诱导的肌成纤维细胞分化和胶原合成通过MRTF-A。NGF-p75（NTR）相互作用的调节代表了纤维化疾病的有希望的疗法。
Myofibroblasts are characterized by de novo expression of a-smooth muscle actin (alpha-SMA) and play a key role in tissue repair and remodeling. In addition to TGF-beta 1, 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(NTR)). Using NIH/3T3 fibroblast cell lines, we examined the induction of myofibroblast differentiation stimulated by NGF. Our findings showed that p75(NTR) was in keeping with the expression of alpha-SMA. Herein, we investigated the role of p75(NTR) in NGF-induced myofibroblast differentiation and collagen synthesis in these cells using lentivirus transfection to overexpress and knock down. Our results showed that p75 NTR was preferentially expressed and was sufficient to induce actin cytoskeleton remodeling, which was required for NGF-induced alpha-SMA expression. Furthermore, NGF induced nuclear translocation of MRTF-A, an effect that was regulated by p75(NTR), and required for alpha-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 alpha-SMA expression. In conclusion, we conclude that p75(NTR) regulates NGF-induced myofibroblast differentiation and collagen synthesis through MRTF-A. Regulation of NGF-p75(NTR) interactions represents a promising therapy for fibrotic disorders.