{"paper_id":"33a02f51-9ebd-4f21-9fe5-95c446b8facc","body_text":"Abstract\nEndometriosis (EMs) is defined as the presence of tissue which somewhat resembles endometrial glands and stroma outside the uterus, and elicits fibrosis. Fibrosis is the main factor resulting in pain and infertility, while the aetiology of endometrial fibrosis is unknown. There is strong evidence from numerous experiments showing that connective tissue growth factor (CCN2) plays a central role in fibrogenesis. Exosomal miR-214-3p can regulate the expression of CCN2 through binding to complementary sites in the 3′ untranslated region. This study aimed to explore the role of exosomal miR-214-3p in endometriosis fibrosis and the relationship between CCN2 and miR-214-3p in endometriosis fibrosis. Our results demonstrated that miR-214-3p was significantly down-regulated and CCN2 was up-regulated in EMs ectopic lesion and stromal cells compared with EMs eutopic and endometrium of patients without endometriosis. Exosomal miR-214-3p can inhibit fibrosis in EMs through targeting CCN2. The results were explored and verified in vitro and in vivo, respectively. Cell co-culture was used to explore the contributions of exosomes to intercellular information transmission of miR-214-3p. The results showed that exosomes play a pivotal role in the transportation of miR-214-3p between cells. Furthermore, level of exosomal miR-214-3p in endometriosis patients’ serum was lower than that in patients without endometriosis. In conclusion, exosomal miR-214-3p can inhibit fibrosis in EMs by targeting CCN2. MiR-214-3p may be considered as a bio-marker and has a potential therapeutic effect in EMs.\nSimilar content being viewed by others\nAbbreviations\n- EMs:\n-\nendometriosis\n- CCN2:\n-\nconnective tissue growth factor\n- TGF-β:\n-\ntransforming growth factor-β\n- HEcESCs:\n-\nhuman ectopic endometrial stromal cells\n- HEuESCs:\n-\nhuman eutopic endometrial stromal cells\n- HEnESCs:\n-\nnormal human endometrial stromal cells\n- a-SMA:\n-\nα-smooth muscle actin\n- coll. α1:\n-\ncollagen α1.\nReferences\nGrande G, Vincenzoni F, Milardi D, et al. Cervical mucus proteome in endometriosis. Clin Proteomics. 2017;14(1):1–7.\nDonnez J, Donnez O, Orellana R, et al. Endometriosis and infertility. Panminerva Med. 2016;88(19):1777–80.\nParisa M, Mehdad N, Sirous Z, et al. Endometriotic mesenchymal stem cells epigenetic pathogenesis:deregulation of miR-200b, miR-145, and let7b in a functional imbalanced epigenetic disease. Cell J. 2019;21(2):179–85.\nGholamali J, Azimeh A. 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BioMed Res Int. 2017;2(7):2931813.\nYing W, Riopel M, Bandyopadhyay G, et al. Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell. 2017;171(2):372–84.\nAcknowledgements\nWe are very grateful to our gynecologcic colleagues for patient recruitment.\nFunding\nNational Natural Science Foundation of China (Grant no. 81771549 Jinwei Miao).\nAuthor information\nAuthors and Affiliations\nContributions\nJinwei Miao proposed the initial experimental conjecture and experimental feasibility analysis. Yanqin Zhang and Di Wu co-completed the experimental technical route writing. Yanqin Zhang completed the cell experiment section, and Xiangyu Chang completed the animal experiment section. Zhaoyu Jin mainly made specific experimental operation instructions and experimental program changes of all experiments. Mengqi Deng mainly did the collection of experimental results and data analysis. Yanqin Zhang and Xiangyu Chang completed together the final article writing and experimental results image modification. All others approved the final article.\nCorresponding author\nEthics declarations\nCompeting Interests\nThe authors declare that they have no conflict of interest.\nEthical Approval and Consent to Participate\nThe study was approved by the Ethics Committee of Beijing Obstetrics and Gynecology Hospital, Capital Medical University, on 10 January 2018 (Ethical approval number:2018-KY-002-01).\nConsent for Publication\nAll authors of this article are responsible for their contributions and agree to publish this article in this magazine.\nAdditional information\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nRights and permissions\nAbout this article\nCite this article\nZhang, Y., Chang, X., Wu, D. et al. Down-regulation of Exosomal miR-214-3p Targeting CCN2 Contributes to Endometriosis Fibrosis and the Role of Exosomes in the Horizontal Transfer of miR-214-3p. Reprod. Sci. 28, 715–727 (2021). https://doi.org/10.1007/s43032-020-00350-z\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s43032-020-00350-z","source_license":"CC0","license_restricted":false}