Unveiling the role of extracellular vesicles in reproductive success and uterine diseases - a systematic review

Extracellular vesicles play a key role in endometrium-embryo communication under both physiological and pathological conditions. This systematic review includes 49 studies that highlight how extracellular vesicles help optimize embryo implantation conditions, and 39 evidencing extracellular vesicle contributions to the pathogenesis of uterine diseases, such as endometriosis, endometrial cancer, recurrent implantation failure (RIF), adenomyosis, uterine leiomyoma and endometritis. Under normal physiological conditions, the protein and microRNA cargo of uterine extracellular vesicles regulated endometrial receptivity, maternal tolerance and embryo development, adhesion and implantation. In endometriosis, extracellular vesicles contributed to pathophysiology via angiogenesis, fibrosis, inflammation, lesion progression and reproduction. Extracellular vesicles promoted endometrial cancer progression and metastasis. In RIF, extracellular vesicles hindered embryo invasiveness, migration, survival and implantation. extracellular vesicles contributed to the progression of adenomyosis, negatively impacting decidualization, implantation and embryo development, whereas in uterine leiomyoma and endometritis, extracellular vesicles affected endometrial receptivity, immune tolerance, blastocyst development, migration and invasion. Overall, uterine extracellular vesicles are key mediators of the endometrium-embryo communication required for successful pregnancy. An altered extracellular vesicle cargo from women with uterine disorders may promote disease progression and associated infertility. Therefore, extracellular vesicles represent potential biomarkers and therapeutic targets for uterine disorders.