Exosomal microRNA-21 derived from bronchial epithelial cells is involved in aberrant epithelium-fibroblast cross-talk in COPD induced by cigarette smoking
Exosomal microRNA-21 derived from bronchial epithelial cells is involved in aberrant epithelium-fibroblast cross-talk in COPD induced by cigarette smoking
复制标题
源自支气管上皮细胞的外泌体 microRNA-21 参与吸烟引起的 COPD 中异常的上皮-成纤维细胞串扰
DOI：
10.7150/thno.27876
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发表时间：
2018-01-01
期刊：
影响因子：
12.4
通讯作者：
Liu, Qizhan
中科院分区：
文献类型：
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作者：
Xu, Hui;Ling, Min;Liu, Qizhan
理由：异常的支气管上皮-成纤维细胞通讯对于导致慢性阻塞性肺病（COPD）的气道重塑至关重要。外泌体已成为细胞间通讯的新型介质，但它们在香烟烟雾（CS）诱导的慢性阻塞性肺病中的作用尚不清楚。在这里，我们研究了外泌体 miR-21 在 CS 引起的功能失调的上皮-成纤维细胞串扰中的作用。方法：将正常或 CS 提取物 (CSE) 处理的人支气管上皮 (HBE) 细胞与支气管成纤维细胞 (MRC-5 细胞) 共培养。使用商业试剂盒从培养基或血清中获得外泌体。使用 ParticleMetrix 的 ZetaView 颗粒追踪器通过纳米颗粒追踪分析来分析外泌体的尺寸分布和浓度。通过尾静脉注射 antagomir-21 到暴露于 CS 的小鼠体内，抑制 miR-21 水平，以证明 miR-21 在导致动物 COPD 的气道重塑中的作用。 结果：对于 MRC-5 细胞，与 CSE 处理的 HBE 细胞或与 CSE 处理的 HBE 细胞衍生的外泌体共培养，导致肌成纤维细胞分化表型。外泌体 miR-21 通过靶向 von Hippel-Lindau 蛋白 (pVHL)，通过缺氧诱导因子 la (HIF-1 α) 信号传导，负责肌成纤维细胞分化； HIF-1 α 转录调节 a-SMA 基因。对于小鼠来说，miR-21 的下调可阻止 CS 诱导的气道重塑。吸烟者和COPD患者血清中外泌体miR-21水平较高，且与FEV1/FVC呈负相关。结论：我们证明CS触发外泌体成分的修饰，并通过pVHL/HIF-1α信号通路鉴定支气管上皮细胞来源的miR-21作为肌成纤维细胞分化的介质，对COPD的诊断和治疗具有潜在价值。
Rationale: Aberrant bronchial epithelium-fibroblast communication is essential for the airway remodeling that contributes to chronic obstructive pulmonary disease (COPD). Exosomes have emerged as novel mediators of intercellular communication, but their role in cigarette smoke (CS)-induced COPD is unknown. Here, we investigated the role of exosomal miR-21 in the dysfunctional epithelium-fibroblast cross-talk caused by CS.Methods: Normal or CS extract (CSE)-treated human bronchial epithelial (HBE) cells were co-cultured with bronchial fibroblasts (MRC-5 cells). Exosomes were obtained from culture media or serum by use of commercial kits. The size distribution and concentration of exosomes were analyzed by nanoparticle tracking analysis using a ZetaView particle tracker from ParticleMetrix. Inhibition of miR-21 levels by tail vein injection of antagomir-21 into mice exposed to CS was used to demonstrate the role of miR-21 in airway remodeling leading to COPD in animals.Results: For MRC-5 cells, co-culture with CSE-treated HBE cells or with exosomes derived from CSE-treated HBE cells resulted in the myofibroblast differentiation phenotype. Exosomal miR-21 was responsible for myofibroblast differentiation through hypoxia-inducible factor la (HIF-1 alpha) signaling by targeting the von Hippel-Lindau protein (pVHL); HIF-1 alpha transcriptionally regulated the a-SMA gene. For mice, downregulation of miR-21 prevented CS-induced airway remodeling. The levels of exosomal miR-21 were high in sera of smokers and COPD patients and inversely correlated with FEV1/FVC.Conclusion: We demonstrate that CS triggers the modification of exosome components and identify miR-21 derived from bronchial epithelial cells as a mediator of myofibroblast differentiation through the pVHL/HIF-1 alpha signaling pathway, which has potential value for diagnosis and treatment of COPD.