Cell Biology and Toxicology ( IF 5.3 ) Pub Date : 2021-08-30 , DOI: 10.1007/s10565-021-09626-9 Mi Ho Jeong 1 , Ha Ryong Kim 2 , Yong Joo Park 3 , Kyu Hyuck Chung 3 , Hyung Sik Kim 3
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Extracellular vesicles (EVs) play novel roles in homeostasis through cell-to-cell communication in human airways via transferring miRNAs. However, the contribution of EV miRNAs to pulmonary phenotypic homeostasis is not clearly understood. Hence, the aim of this study was to elucidate the functional role of miRNAs obtained from epithelium-derived EVs in lung fibrogenesis. Pulmonary fibrosis was induced by exposure of polyhexamethylene guanidine phosphate (PHMG-p)-instilled mice. In histopathological changes, a clear phenotypic change was observed in bronchial epithelium. For figuring out the role of EVs derived from conditioned media of untreated cells (EV-Con) and PHMG-p-treated BEAS-2B (EV-PHMG), significant increase in EVs released from PHMG-p-treated BEAS-2B was detected. Functional analysis with targets of differentially expressed miRNAs in EVs was annotated to epithelial–mesenchymal transition (EMT). Especially, the most abundant miRNA, miR-451a, was downregulated in EV of PHMG-p-treated BEAS-2B cells. We found that odd-skipped related 1 (OSR1) was a putative target for miR-451a, which had been known as a transcription factor of several fibrosis-associated genes. Transfer of decreased miR-451a via EV-PHMG upregulated OSR1 and induced EMT compared to Con-EV-treated cells. In pulmonary fibrosis mice, miR-451a levels were significantly reduced in EV derived from bronchoalveolar lavage fluid and OSR1 expression was increased in lung tissues of mice with PHMG-p exposure. MiR-451a-transfected EVs markedly alleviated fibrogenesis in the PHMG-p-exposed lungs. Low level of miR-451a in EVs modulated EMT and fibrogenesis in recipient cells by increasing OSR1 levels in vitro and in vivo. Our results suggest that transferring EV miR-451a induces anti-fibrotic autocrine effect by downregulating its target, OSR1 maintaining pulmonary homeostasis disrupted by PHMG-p exposure, which can be a potential therapeutic target.
Graphical abstract
中文翻译：
通过减少细胞外囊泡中的 miR-451a 重编程肺上皮细胞有助于肺纤维化的加重
细胞外囊泡 (EV) 通过转移 miRNA 在人体气道中的细胞间通讯在体内平衡中发挥新的作用。然而，EV miRNA 对肺表型稳态的贡献尚不清楚。因此，本研究的目的是阐明从上皮衍生的 EV 中获得的 miRNA 在肺纤维化中的功能作用。肺纤维化是由暴露于聚六亚甲基胍磷酸 (PHMG-p) 滴注的小鼠引起的。在组织病理学变化中，在支气管上皮中观察到明显的表型变化。为了弄清楚源自未处理细胞 (EV-Con) 和 PHMG-p 处理的 BEAS-2B (EV-PHMG) 的条件培养基的 EV 的作用，检测到从 PHMG-p 处理的 BEAS-2B 释放的 EV 显着增加. 对 EV 中差异表达 miRNA 靶点的功能分析注释为上皮-间质转化 (EMT)。特别是，最丰富的 miRNA，miR-451a，在 PHMG-p 处理的 BEAS-2B 细胞的 EV 中被下调。我们发现奇数跳过相关 1 (OSR1) 是 miR-451a 的推定靶标，miR-451a 被认为是几种纤维化相关基因的转录因子。与 Con-EV 处理的细胞相比，通过 EV-PHMG 转移减少的 miR-451a 上调 OSR1 并诱导 EMT。在肺纤维化小鼠中，来自支气管肺泡灌洗液的 EV 中 miR-451a 水平显着降低，并且在 PHMG-p 暴露的小鼠肺组织中 OSR1 表达增加。MiR-451a 转染的 EV 显着减轻了暴露于 PHMG-p 的肺中的纤维化。EVs 中低水平的 miR-451a 通过在体外和体内增加 OSR1 水平来调节受体细胞中的 EMT 和纤维化。我们的研究结果表明，转移 EV miR-451a 通过下调其靶点（OSR1 维持被 PHMG-p 暴露破坏的肺稳态）诱导抗纤维化自分泌效应，这可能是一个潜在的治疗靶点。
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