Ectopic Endometrial Cell-Derived Exosomal Moesin Induces Eutopic Endometrial Cell Migration, Enhances Angiogenesis and Cytosolic Inflammation in Lesions Contributes to Endometriosis Progression

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 in particular, play a critical role in developing various clinical disorders. However, the implication of exosomes in endometriosis progression has not been well elucidated.Method: The ectopic stromal cellular exosomes (eEVs) were assessed by transwell assay, scratch tests, tube formation assay, western blot, and qRT-PCR analysis. Protein expression profiles of exosomes in endometrial tissue and vaginal discharge collected from patients with EMS and healthy donors were analysed by Mass spectrometry. siRNA interference technology was used to inhibit the expression of exosomal protein for the functional analysis in in-vivo. Finally, in-vitro experiments were performed to validate the results that we observed in EMs mouse model.Results:In vitro, we discovered that eEVs improved NSC migratory potential by upregulating MMP9 expression and activity. eEVs also aided angiogenesis and elevated the expression of inflammatory cytokines in ovarian epithelial cells, according to our findings. Moesin (MSN) levels in ESC exosomes were substantially greater than in NSC exosomes (1.22e8±5.58e6 vs. 6.605e7±4.574e6, LFQ intensity), as shown by protein mass spectrometry and bioinformatics analysis. In ectopic stromal cells, ERa receptors stimulated the RhoA/Rock-2/MSN pathway. We discovered that downregulating exosomal moesin reduced NSC migration (about 3-fold change) and MMP9 expression (about 2-fold change). On the other hand, Exomsni inhibited angiogenesis and inflammatory cytokine release. In vivo the result of immunohistochemistry and immunofluorescence demonstrated that exosomal MSN substantially modified the expression of MM9, VEGFR and p-VEGFR in polyclonal lesions. In addition, we discovered an elevation in the expression of proinflammatory factors in the surrounding tissue.Conclusion: Exosomal MSN derived from ectopic stromal cells can contribute to endometriosis progression by mediating the construction of a “migration-vascularization-inflammation” loop in the ectopic environment.

Extracellular vesicles in endometriosis: role and potential

“…This process mediates the exchange of information between cells. In the context of EMs, ESCs, macrophages, and mesenchymal stem cells (MSCs) engage in communication through EVs that carry specific substances (36)(37)(38). These EVs mediate various signaling pathways, ultimately promoting the progression of EMs.…”

“…ESCs play a key role in the development of EMs by releasing EVs containing specific substances that stimulate surrounding ESCs and other recipient cells, thereby promoting angiogenesis, fibrosis, and mediating EMs. For example, Abudula et al found that EVs derived from ESCs induced normal endometrial stromal cell migration, angiogenesis, and upregulation of inflammatory cytokine expression in ovarian cells (36). Li et al found that EVs derived from ectopic ESCs (eESCs) promote lymphangiogenesis (39).…”

“…These EVs, carrying moesin, are delivered to normal ESCs. Within these recipient cells, moesin mediates the establishment of a "migrationvascularization-inflammation" loop in the ectopic environment, thereby promoting the progression of EMs (36). Sun et al discovered that EVs play a crucial role in the progression of EMs by promoting the co-recruitment of nerves and blood vessels, inducing neurite outgrowth, and inhibiting neuronal apoptosis (41).…”

The Extracellular Vesicle–Macrophage Regulatory Axis: A Novel Pathogenesis for Endometriosis

“…The blocking of EVs reduces pro-neuro angiogenesis induced by EVs, indicating that EVs play an important role in neuro-angiogenesis in EMs [ 53 ]. Qiu et al demonstrated that enriched lncRNA aHIF from ESCs-derived EVs can facilitate the angiogenesis of EMs by activating vascular endothelial growth factor (VEGF)-A, VEGF-D and basic fibroblast growth factor [ 42 , 54 , 55 ]. In addition, the expression of miR-15a-5p in EVs from ovarian ectopic endometrium was downregulated [ 43 ].…”