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Exosomal miR-218 derived from mesenchymal stem cells inhibits endothelial-to-mesenchymal transition by epigenetically modulating of BMP2 in pulmonary fibrosis

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Abstract

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.

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Data availability

The datasets presented in the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 81974219 and 82101650), the Science and Technology Commission of Shanghai Municipality (No. 19DZ1204404, 20YF1429000, 21YF1436800, 21ZR1441200, and 22ZR1440900), and Shanghai Municipal Health Commision (No. 20204Y0419 and 202140044). The granting body had no role in the study design, data collection, data analysis, data interpretation, and the writing of the report or decision to submit the paper.

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Author notes

  1. Yuhao Zhao, Lei Du, and Jiali Sun contributed equally to this work.

Authors and Affiliations

  1. Department of Geriatrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kong Jiang Road, Shanghai, 200092, China

    Yuhao Zhao, Lei Du, Jiali Sun, Xuelian Wang, Shuyan Chen, Fei Wang & Zhen Li

  2. Department of Emergency, Huashan Hospital Affiliated to Fudan University, Shanghai, China

    Zhilei Cong

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  1. Yuhao Zhao
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Contributions

Y.Z., L.D., and J.S. performed most of the experiments, collected, and analyzed the data. X.W. and Z.C. participated in acquiring and analyzing the data. S.C. and F.W. designed the study and drafted the manuscript. Z.L. supervised the study and edited the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Shuyan Chen, Fei Wang or Zhen Li.

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The animal study was approved by the Ethics Committee of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine.

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Graphical Headlights

1. hucMSC-Exos possess anti-fibrotic properties through the delivery of miR-218 into HMEC.

2. Exosomal miR-218 inhibits EndMT through MeCP2/BMP2 pathway.

3. MeCP2 promotes EndMT by epigenetic modulation of BMP2.

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Zhao, Y., Du, L., Sun, J. et al. Exosomal miR-218 derived from mesenchymal stem cells inhibits endothelial-to-mesenchymal transition by epigenetically modulating of BMP2 in pulmonary fibrosis. Cell Biol Toxicol 39, 2919–2936 (2023). https://doi.org/10.1007/s10565-023-09810-z

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