Endothelial-to-mesenchymal transition (EndMT), the process by which endothelial cells lose their characteristics and acquire mesenchymal phenotypes, participates in the pathogenic mechanism of idiopathic pulmonary fibrosis. Recently, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-Exos) has been introduced as a promising treatment in organ fibrosis. This study aimed to explore the effects as well as the molecular mechanism for hucMSC-Exo in pulmonary fibrosis. The intravenous administration of hucMSC-Exos alleviated bleomycin-induced pulmonary fibrosis in vivo. Moreover, hucMSC-Exos elevated miR-218 expression and restored endothelial properties weakened by TGF-β in endothelial cells. Knockdown of miR-218 partially abrogated the inhibition effect of hucMSC-Exos on EndMT. Our mechanistic study further demonstrated that MeCP2 was the direct target of miR-218. Overexpressing MeCP2 aggravated EndMT and caused increased CpG islands methylation at BMP2 promoter, which lead to BMP2 post-transcriptional gene silence. Transfection of miR-218 mimic increased BMP2 expression as well, which was downregulated by overexpression of MeCP2. Taken together, these findings indicate exosomal miR-218 derived from hucMSCs may possess anti-fibrotic properties and inhibit EndMT through MeCP2/BMP2 pathway, providing a new avenue of preventive application in pulmonary fibrosis.

Graphical abstract

中文翻译：

---

间充质干细胞来源的外泌体 miR-218 通过表观遗传调节肺纤维化中的 BMP2 抑制内皮-间质转化

内皮-间质转化 (Endothelial-to-mesenchymal transition, EndMT) 是内皮细胞失去其特性并获得间充质表型的过程，参与了特发性肺纤维化的致病机制。最近，源自人脐带间充质干细胞 (hucMSC-Exos) 的外泌体已被引入作为器官纤维化的有前途的治疗方法。本研究旨在探讨hucMSC-Exo在肺纤维化中的作用及分子机制。静脉注射 hucMSC-Exos 可减轻体内博来霉素诱导的肺纤维化。此外，hucMSC-Exos 提高了 miR-218 的表达并恢复了内皮细胞中被 TGF-β 削弱的内皮特性。miR-218 的敲低部分消除了 hucMSC-Exos 对 EndMT 的抑制作用。我们的机理研究进一步证明 MeCP2 是 miR-218 的直接靶标。过表达 MeCP2 加重了 EndMT 并导致 BMP2 启动子处的 CpG 岛甲基化增加，从而导致 BMP2 转录后基因沉默。miR-218 模拟物的转染也增加了 BMP2 的表达，其被 MeCP2 的过表达下调。总之，这些发现表明来自 hucMSCs 的外泌体 miR-218 可能具有抗纤维化特性，并通过 MeCP2/BMP2 途径抑制 EndMT，为肺纤维化的预防应用提供了新途径。它被 MeCP2 的过表达下调。总之，这些发现表明来自 hucMSCs 的外泌体 miR-218 可能具有抗纤维化特性，并通过 MeCP2/BMP2 途径抑制 EndMT，为肺纤维化的预防应用提供了新途径。它被 MeCP2 的过表达下调。总之，这些发现表明来自 hucMSCs 的外泌体 miR-218 可能具有抗纤维化特性，并通过 MeCP2/BMP2 途径抑制 EndMT，为肺纤维化的预防应用提供了新途径。

图形概要