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

Yanqin Zhang, Xiangyu Chang, Di Wu, Mengqi Deng, Jinwei Miao, Zhaoyu Jin
Reproductive sciences (Thousand Oaks, Calif.) · 2020 · vol. 28(3) , pp. 715–727 · doi:10.1007/s43032-020-00350-z · PMID:33048316 · W3092517164
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Exosomal miR-214-3p, down-regulated in endometriosis, inhibits fibrosis by targeting CCN2 and is transferred between cells via exosomes.

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The paper studied how exosomal miR-214-3p and its target CCN2 contribute to endometriosis-associated fibrosis, using patient-derived ectopic and eutopic lesion/stromal samples and complementary in vitro and in vivo experiments. The authors found that miR-214-3p was significantly down-regulated while CCN2 was up-regulated in endometriosis ectopic lesions and stromal cells versus eutopic endometrium from patients without endometriosis, and that exosomal miR-214-3p inhibited fibrosis in endometriosis by targeting CCN2. Using cell co-culture, they reported that exosomes are pivotal for transporting miR-214-3p between cells, and they observed lower exosomal miR-214-3p levels in the serum of patients with endometriosis. This paper explicitly discusses endometriosis — it centers on exosomal miR-214-3p/CCN2 mechanisms regulating endometriosis fibrosis.

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Abstract

Endometriosis (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. Similar content being viewed by others Abbreviations - EMs: - endometriosis - CCN2: - connective tissue growth factor - TGF-β: - transforming growth factor-β - HEcESCs: - human ectopic endometrial stromal cells - HEuESCs: - human eutopic endometrial stromal cells - HEnESCs: - normal human endometrial stromal cells - a-SMA: - α-smooth muscle actin - coll. α1: - collagen α1.

References

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Acknowledgements

We are very grateful to our gynecologcic colleagues for patient recruitment. Funding National Natural Science Foundation of China (Grant no. 81771549 Jinwei Miao). Author information Authors and Affiliations Contributions Jinwei 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. Corresponding author Ethics declarations Competing Interests The authors declare that they have no conflict of interest. Ethical Approval and Consent to Participate The 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). Consent for Publication All authors of this article are responsible for their contributions and agree to publish this article in this magazine. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions About this article Cite this article Zhang, 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 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-020-00350-z

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endometriosis

MeSH descriptors

Connective Tissue Growth Factor Endometriosis Endometrium Exosomes MicroRNAs Stromal Cells Animals Case-Control Studies Cells, Cultured Connective Tissue Growth Factor Connective Tissue Growth Factor Disease Models, Animal Endometriosis Endometriosis Endometriosis Endometrium Endometrium Exosomes Exosomes Exosomes

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