MICAL2 regulates myofibroblasts differentiation in epidural fibrosis via SRF/MRTF-A signaling pathway
MICAL2 regulates myofibroblasts differentiation in epidural fibrosis via SRF/MRTF-A signaling pathway
复制标题
MIACL2 通过 SRF/MRTF-A 信号通路调节硬膜外纤维化中的肌成纤维细胞分化。
DOI：
10.1016/j.lfs.2021.119045
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发表时间：
2021
期刊：
影响因子：
6.1
通讯作者：
Cao Xiaojian
中科院分区：
文献类型：
--
作者：
Jiang Fan;Cao Jiang;Kong Renyi;Fang Le;Wang Binyu;Zhang Sheng;Yang Lei;Cao Xiaojian
目的探讨MICAL 2在肌成纤维细胞分化和硬膜外纤维化中的作用。致密硬膜外纤维化导致手术效果差和腰椎手术失败综合征，目前尚无有效的治疗方法。与Cas 12相互作用的分子（MICAL 2）已被证明通过调节肌动蛋白细胞骨架动力学参与多种细胞过程。然而，其在硬膜外纤维化中的作用仍然完全未得到证实。材料和方法MICAL 2的潜在功能和机制进行了探讨，使用Western印迹，免疫荧光和慢病毒infection.Key findsIn我们的研究中，我们确定了MICAL 2的表达在硬膜外纤维化组织和TGF-β1刺激的成纤维细胞中升高。此外，使用MICAL 2特异性短发夹RNA敲低MICAL 2在体外和体内均减弱TGF-β1诱导的肌成纤维细胞分化和硬膜外纤维化，如减少的瘢痕形成，减少的胶原产生和下调的α-SMA、胶原-1和FN的表达所示。我们还证明了MICAL 2敲低影响体外成纤维细胞的迁移能力。通过进一步的机制研究，我们揭示了MICAL 2在成纤维细胞中的敲低可抑制MRTF-A核转位，MICAL 2以SRF/MRTF-A依赖的方式作为促纤维化因子。提示操纵MICAL 2活性是预防硬膜外纤维化的一种新的替代策略。
AimTo determine the role of MICAL2 in myofibroblasts differentiation and epidural fibrosis.BackgroundEpidural fibrosis (EF) may develop following laminectomy and aberrant myofibroblasts differentiation and excessive extracellular matrix (ECM) accumulation play key roles in the formation of EF. Dense epidural fibrosis results to the poor surgical outcomes and failed back surgery syndrome (FBSS), and there is no effective treatment available. Molecule interacting with Casl2 (MICAL2) has been demonstrated to participate in multiple cellular processes by regulating actin cytoskeleton dynamics. However, its role in epidural fibrosis remains totally unverified.Materials and methodsThe potential functions and mechanisms of MICAL2 were explored using western blotting, immunofluorescence and lentivirus infection.Key findingsIn our study, we determined that the MICAL2 expression was elevated in epidural fibrotic tissues and TGF-β1-stimulated fibroblasts. Moreover, knockdown of MICAL2 using MICAL2-specific short hairpin RNA attenuated TGF-β1-induced myofibroblasts differentiation and epidural fibrosis both in vitro and vivo, as indicated by decreased scar formation, reduced collagen production and down-regulated expression of α-SMA, collagen-1 and fibronectin. We also demonstrated that MICAL2 knockdown affected the migratory capability of fibroblasts in vitro. By further mechanistic research, we revealed that the MRTF-A nuclear translocation was inhibited in response to the knockdown of MICAL2 in fibroblasts and MICAL2 served as a pro-fibrotic factor in an SRF/MRTF-A-dependent manner.SignificanceIn conclusion, our results indicated that MICAL2 mediated myofibroblasts differentiation and promoted epidural fibrogenesis via SRF/MRTF-A signaling pathway, suggesting manipulation of MICAL2 activity as a novel alternative strategy for the prevention of epidural fibrosis.