Exosomal Moesin Derives From Ectopic Stromal Cells Constructs A “Migration-Vascularization-Inflammation” Loop In Endometriosis

Abstract

Background: Endometriosis (EMS) is the most common gynaecological disorder with its etiology and/or pathophysiology remains enigmatic. Recent studies showed that extracellular vesicles (EVs), exosomes namely, play a critical role in the development of various clinical disorders, including inflammatory disease and cancers. Previous studies revealed the role of exosomes as a potential biomarker in EMS. However, the implication of exosomes in the disease progression of EMS has not been well elucidated. Method: The biological function of ectopic exosomes (eEVs) was examined by Transwell assay, scratch tests, tube formation assay, western blot, and qRT-PCR analysis. Mass spectrometry analysis of the exosomes isolated from fresh EMS tissue and vaginal discharge obtained from patients with and without EMS used to identify differentially expressed protein in exosomes from ectopic stromal cells (ESCs) and normal endometrial stromal cells (NESCs). Gene knockdown was used to downregulate the expression of exosomal protein in in-vivo setting. Finally, in-vitro experiment confirmed the results that we observed in endometriosis (EMS) mouse model. Results: We found that eEVs increased the migration ability of NESCs) by up-regulating MMP9 expression. We also observed that eEVs facilitate angiogenesis, and induced the high expression of inflammatory cytokines in ovarian epithelial cells. Protein Mass spectrometry and bioinformatics analysis showed that Moesin (MSN) is highly expressed in eEVs. An abnormal high estrogen environment may up-regulate MSN expression in ectopic lesion. Downregulation of exosomal Moesin attenuated the migration capability of normal endometrium, inhibited angiogenesis, and reduced the expression of inflammatory cytokine. Moreover, we found that ectopic exosomes significantly increased the number and size of heterotopic foci in vivo. Also, we observed an increase in the size of vascular lumen, and upregulation of inflammatory factors expression in small intestine adjacent to the heterotopic foci. Conclusion: Exosomal MSN from ectopic stromal cells could contribute to the development of EMS by mediating the construction of a “migration-vascularization-inflammation” loop in ectopic environment.