The Biological Function of Extracellular Vesicles during Fertilization, Early Embryo-Maternal Crosstalk and Their Involvement in Reproduction: Review and Overview

Abstract

Secretory extracellular vesicles (EVs) are membrane-enclosed microparticles that mediate cell to cell communication in proximity to, or distant from, the cell of origin. Cells release a heterogeneous spectrum of EVs depending on their physiologic and metabolic state. Extracellular vesicles are generally classified as either exosomes or microvesicles depending on their size and biogenesis. Extracellular vesicles mediate temporal and spatial interaction during many events in sexual reproduction and supporting embryo-maternal dialogue. Although many omic technologies provide detailed understanding of the molecular cargo of EVs, the difficulty in obtaining populations of homogeneous EVs makes difficult to interpret the molecular profile of the molecules derived from a miscellaneous EV population. Notwithstanding, molecular characterization of EVs isolated in physiological and pathological conditions may increase our understanding of reproductive and obstetric diseases and assist the search for potential non-invasive biomarkers. Moreover, a more precise vision of the cocktail of biomolecules inside the EVs mediating communication between the embryo and mother could provide new insights to optimize the therapeutic action and safety of EV use.

Keywords: biomarker; diagnosis; embryo; exosomes; extracellular vesicles; miRNA; microvesicles; protein; reproduction; therapy.

Figure 1

Overview of the main procedures used for the isolation, characterization and clinical use of extracellular vesicles (EVs). (1) Extracellular vesicles are released by cells into the culture media or from tissue into the extracellular environment. (2) Extracellular vesicles are separated or further purified to obtain a more homogeneous EV population using a variety of methods. (3) Isolated EVs are physically characterized by: Scanning Electron Microscopes (SEM), Transmission Electron Microscopes (TEM), Nanoparticle Tracking Analysis (NTA) and Dynamic Light Scattering (DLS). (4) Extracellular vesicles are molecularly characterized using several techniques. (5) Biomarkers can be obtained by molecular profiling of isolated EVs from in vitro cell cultures or body fluids in pathologic condition and used as diagnostic tools for several human and veterinary diseases. Isolated EVs can also be used as treatments in human and veterinary medicine.

Figure 2

Graphical representation of the EVs mediated cross-talk interaction in the female reproductive system. (1) Seminal plasma EVs (spEVs) interact with endometrium (2) oviductal tract EVs (oEVs)with sperm (2a) and embryo (2b),(3) follicular fluids EVs (ffEVs) with embryo (4) embryo EVs (eEVs) with endometrium (5) placenta EVs (pEVs)with extravillous trophoblasts (6) endometrium EVs (endEVs) with embryo. Colored dashed line (and numbers) indicates EVs release and uptake from donor and recipient cells or tissue, which studies are reported in Table 2. In figure, the human female reproductive tract was shown as example of mammalian female reproductive system.