Extracellular vesicle research in reproductive science: Paving the way for clinical achievements

Abstract

Mammalian conception involves a multitude of reciprocal interactions via a molecular dialogue between mother and conceptus. Extracellular vesicles (EVs) are secreted membrane-encapsulated particles that mediate cell-to-cell communication in various contexts. EVs, which are present in seminal, follicular, oviductal, and endometrial fluids, as well as in embryo secretions, carry molecular constituents that impact gamete maturation, fertilization, early embryo development, and embryo-maternal communication. The distribution, concentration, and molecular cargo of EVs are regulated by steroid hormones and the health status of the tissue of origin, and thus are influenced by menstrual phase, stage of conception, and the presence of infertility-associated diseases. EVs have been recognized as a novel source of biomarkers and potential reproductive medicine therapeutics, particularly for assisted reproductive technology (ART). There are still many technological and scientific hindrances to be overcome before EVs can be used in clinical diagnostic and therapeutic ART applications. Issues to be resolved include the lack of standardized measurement protocols and an absence of absolute EV quantification technologies. Additionally, clinically suitable and robust EV isolation methods have yet to be developed. In this review, we provide an overview of EV-mediated interactions during the early stages of reproduction from gamete maturation to embryo implantation and then outline the technological progress that must be made for EV applications to be translated to clinical settings.

Cellular and Molecular Nature of Fragmentation of Human Embryos

“…In contrast to exosome formation, the secretion of microvesicles requires the lipid microdomains at the membrane and a reorganization of the actin-myosin cytoskeletal network [97,98]. A possible association between the EV quantity in the spent culture media and embryo quality and competence has been suggested [99][100][101]. Specifically, fewer EVs have been reported in spent culture media of embryos leading to successful pregnancy than in those who failed, suggesting that a good quality and competent embryo releases different amounts/types of EVs compared to a low-quality embryo [102][103][104][105].…”

Extracellular Vesicles as Novel Drug-Delivery Systems through Intracellular Communications

“…The MVEs fuse with lysosomes to degrade their cargo, including their ILVs, by hydrolases [48][49][50]. However, after the fusion of late endosomes and MVBs with cell membranes, their ILVs are released into the extracellular space as exosomes, which are detected in different biological fluids, such as cerebrospinal fluid, saliva, blood, breast milk, amniotic fluid, seminal fluid, and urea (Figure 2) [51][52][53][54][55][56][57].…”

“…The MVEs fuse with lysosomes to degrade their cargo, including t ILVs, by hydrolases [48][49][50]. However, after the fusion of late endosomes and MVBs w cell membranes, their ILVs are released into the extracellular space as exosomes, wh are detected in different biological fluids, such as cerebrospinal fluid, saliva, blood, br milk, amniotic fluid, seminal fluid, and urea (Figure 2) [51][52][53][54][55][56][57]. Upon the binding of ligand with some, the endocytosis process involves inward budding of the cell membrane, which occurs at l rafts containing common membrane proteins, such as tetraspanins (e.g., CD9, CD81, CD63, e MHC class I and class II, and adhesion molecules (e.g., integrins, cadherins, etc.).…”

Role of extracellular vesicles in intercellular communication during reproduction

“…Studies report that competent embryos produce different populations of EVs compared with degenerating embryos, and their effects on maternal system are quantifiably different (Dissanayake et al, 2020(Dissanayake et al, , 2021Godakumara et al, 2021). Similarly, analysing the EVs produced by maternal tissue could also be a non-invasive method to determine the state of receptivity (Aleksejeva et al, 2022;Luddi et al, 2019). There have been efforts to use EVs as therapeutic agents in mammalian reproductive pathologies such as polycystic ovary syndrome, endometriosis and preeclampsia (Esfandyari et al, 2021).…”