Suppression of autophagy by extracellular vesicles promotes myofibroblast differentiation in COPD pathogenesis.
Suppression of autophagy by extracellular vesicles promotes myofibroblast differentiation in COPD pathogenesis.
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DOI：
10.3402/jev.v4.28388
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发表时间：
2015
影响因子：
16
通讯作者：
Ochiya T
中科院分区：
文献类型：
--
作者：
Fujita Y;Araya J;Ito S;Kobayashi K;Kosaka N;Yoshioka Y;Kadota T;Hara H;Kuwano K;Ochiya T
细胞外小泡(EV)，如外切小体和微囊泡，包裹着蛋白质和microRNAs(MiRNAs)，作为细胞间串扰和疾病发病机制的新调节器。EVS的组成被各种触发因素改变，以维持生理内平衡。暴露在香烟烟雾中，肺部会出现肺气肿、肌成纤维细胞堆积和呼吸道重塑，这些都会导致慢性阻塞性肺疾病(COPD)。然而，通过改良EVS在应激生理学中对肺部疾病的发病机制尚不清楚。在这里，我们研究了EV介导的原代人支气管上皮细胞(HBECs)和肺成纤维细胞(LFS)之间的细胞间通讯机制，发现香烟烟雾提取物(CSE)诱导的HBEC来源的EV促进LFS的肌成纤维细胞分化。对改良的EVS和COPD肺样本的彻底评估表明，香烟烟雾诱导了支气管上皮细胞和EV miR-210表达的相对上调。通过共培养实验，我们发现HBEC来源的EV miR-210促进了LFS中肌成纤维细胞的分化。令人惊讶的是，我们发现miR-210通过靶向ATG7直接调节自噬过程，并且在LFS中miR-210的表达水平与ATG7的表达水平呈负相关。重要的是，COPD患者LFS的自噬诱导显著减少，沉默LFS中的ATG7导致肌成纤维细胞分化。这些发现表明CSE触发EV成分的修饰，并确定支气管上皮细胞来源的miR-210是肌成纤维细胞分化的旁分泌自噬介质，有可能成为COPD的治疗靶点。我们的发现表明，应激源暴露会作为新兴因素改变EV成分，潜在地控制COPD患者的气道重塑等病理疾病。
Extracellular vesicles (EVs), such as exosomes and microvesicles, encapsulate proteins and microRNAs (miRNAs) as new modulators of both intercellular crosstalk and disease pathogenesis. The composition of EVs is modified by various triggers to maintain physiological homeostasis. In response to cigarette smoke exposure, the lungs develop emphysema, myofibroblast accumulation and airway remodelling, which contribute to chronic obstructive pulmonary disease (COPD). However, the lung disease pathogenesis through modified EVs in stress physiology is not understood. Here, we investigated an EV-mediated intercellular communication mechanism between primary human bronchial epithelial cells (HBECs) and lung fibroblasts (LFs) and discovered that cigarette smoke extract (CSE)-induced HBEC-derived EVs promote myofibroblast differentiation in LFs. Thorough evaluations of the modified EVs and COPD lung samples showed that cigarette smoke induced relative upregulation of cellular and EV miR-210 expression of bronchial epithelial cells. Using co-culture assays, we showed that HBEC-derived EV miR-210 promotes myofibroblast differentiation in LFs. Surprisingly, we found that miR-210 directly regulates autophagy processes via targeting ATG7, and expression levels of miR-210 are inversely correlated with ATG7 expression in LFs. Importantly, autophagy induction was significantly decreased in LFs from COPD patients, and silencing ATG7 in LFs led to myofibroblast differentiation. These findings demonstrate that CSE triggers the modification of EV components and identify bronchial epithelial cell-derived miR-210 as a paracrine autophagy mediator of myofibroblast differentiation that has potential as a therapeutic target for COPD. Our findings show that stressor exposure changes EV compositions as emerging factors, potentially controlling pathological disorders such as airway remodelling in COPD.