Extensive evidence suggests that the release of membrane-enclosed compartments, more commonly known as extracellular vesicles (EVs), is a potent newly identified mechanism of cell-to-cell communication both in normal physiology and in pathological conditions. This review presents evidence about the formation and release of different EVs, their definitive markers and cargo content in reproductive physiological processes, and their capacity to convey information between cells through the transfer of functional protein and genetic information to alter phenotype and function of recipient cells associated with reproductive biology. In the male reproductive tract, epididymosomes and prostasomes participate in regulating sperm motility activation, capacitation, and acrosome reaction. In the female reproductive tract, follicular fluid, oviduct/tube, and uterine cavity EVs are considered as vehicles to carry information during oocyte maturation, fertilization, and embryo-maternal crosstalk. EVs via their cargo might be also involved in the triggering, maintenance, and progression of reproductive- and obstetric-related pathologies such as endometriosis, polycystic ovarian syndrome, preeclampsia, gestational diabetes, and erectile dysfunction. In this review, we provide current knowledge on the present and future use of EVs not only as biomarkers, but also as therapeutic targeting agents, mainly as vectors for drug or compound delivery into target cells and tissues.
Extracellular vesicles (EVs) are known to transport DNA, but their implications in embryonic implantation are unknown. The aim of this study was to investigate EVs production and secretion by preimplantation embryos and assess their DNA cargo. Murine oocytes and embryos were obtained from six- to eight-week-old females, cultured until E4.5 and analyzed using transmission electron microscopy to examine EVs production. EVs were isolated from E4.5-day conditioned media and quantified by nanoparticle tracking analysis, characterized by immunogold, and their DNA cargo sequenced. Multivesicular bodies were observed in murine oocytes and preimplantation embryos together with the secretion of EVs to the blastocoel cavity and blastocyst spent medium. Embryo-derived EVs showed variable electron-densities and sizes (20–500 nm) and total concentrations of 1.74 × 107 ± 2.60 × 106 particles/mL. Embryo secreted EVs were positive for CD63 and ARF6. DNA cargo sequencing demonstrated no differences in DNA between apoptotic bodies or smaller EVs, although they showed significant gene enrichment compared to control medium. The analysis of sequences uniquely mapping the murine genome revealed that DNA contained in EVs showed higher representation of embryo genome than vesicle-free DNA. Murine blastocysts secrete EVs containing genome-wide sequences of DNA to the medium, reinforcing the relevance of studying these vesicles and their cargo in the preimplantation moment, where secreted DNA may help the assessment of the embryo previous to implantation.
The transmission of DNA through extracellular vesicles (EVs) represents a novel genetic material transfer mechanism that may impact genome evolution and tumorigenesis. We aimed to investigate the potential for vertical mitochondrial (mt)DNA transmission within maternal endometrial EVs to the pre-implantation embryo and describe any effect on embryo bioenergetics. We discovered that the human endometrium secretes all three general subtypes of EV - apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXOs) - into the human endometrial fluid (EF) within the uterine cavity. EVs become uniformly secreted into the EF during the menstrual cycle, with the proportion of different EV populations remaining constant; however, MVs contain significantly higher levels of DNA than ABs or EXOs. During the window of implantation, MVs contain an eleven-fold higher level of mtDNA when compared to cells-of-origin within the receptive endometrium, which possesses a lower mtDNA content and displays the upregulated expression of mitophagy-related genes. Furthermore, we demonstrate the internalization of EV-derived mtDNA by trophoblast cells of murine embryos, which associated with a reduction in mitochondrial respiration and ATP production. These findings suggest that the maternal endometrium suffers a reduction in mtDNA content during the preconceptional period, that mtDNA becomes packaged into secreted EVs that the embryo uptakes, and that the transfer of mtDNA to the embryo within EVs occurs alongside the modulation of bioenergetics during implantation.
OBJECTIVE: The diagnosis of endometrial receptivity is being used as a clinical test to manage the endometrial factor in patients with implantation failure. Yet, this procedure is invasive and it delays personalized embryo transfer (pET) until the next cycle. We aim to develop a non-invasive approach based on the analysis of the transcriptomic signature in the endometrial fluid (EF).DESIGN: Fifty-six patients with implantation failure that underwent Endometrial Receptivity Analysis (ERA) test leading to successful pET, and the transcriptomic signature of their paired EF samples was analyzed blindly to compare receptivity diagnoses.MATERIALS AND METHODS: EF was aspirated immediately before endometrial biopsy using a flexible catheter (Wallace, SMI) inserted into the uterine cavity obtaining 10-20 ml of EF per patient that were snap frozen and stored. RNA was extracted using RNeasy mini-kit (Qiagen) and qualitychecked using Fragment Analyzer (AATI, USA). Gene expression was analysed using Ion AmpliSeq RNA for ERA custom panel in an Ion S5 system (Life Tech, USA) coupled to a computational predictor.RESULTS: Paired samples of EF and endometrial biopsy from the same patients (n¼56) were analysed separately. In 13 EF samples (23.2%) RNA quantity and/or quality were poor (mean: concentration 28.5 ng/ml; RIN 1.75). The remaining 43 EFs (76.8%) with mean concentration of 108.3 ng/ml and RIN of 4.3, generated good-quality libraries for sequencing. These 43 EFs yielded results concordant with their paired endometrial biopsies analysed by ERA: 33 were confirmed receptive (76.7%), 7 pre-receptive (16.3%), and 3 post-receptive (7.0%). EF testing resulted in 100% sensitivity and specificity with no false positive or negatives vs ERA.CONCLUSIONS: Transcriptomic profiling of EF samples gave high sensitivity and specificity vs the invasive test. Technical improvement in the collection and shipment of EF is necessary to avoid RNA degradation. Thus, EF offers a non-invasive alternative to diagnose endometrial receptivity for personalized embryo transfer without a need for endometrial biopsy.
The transmission of DNA through extracellular vesicles (EVs) represents a novel genetic material transfer mechanism that may impact genome evolution and tumorigenesis. We aimed to investigate the potential for vertical mitochondrial (mt)DNA transmission within maternal endometrial EVs to the pre-implantation embryo and describe any effect on embryo bioenergetics. We discovered that the human endometrium secretes all three general subtypes of EV - apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXOs) - into the human endometrial fluid (EF) within the uterine cavity. EVs become uniformly secreted into the EF during the menstrual cycle, with the proportion of different EV populations remaining constant; however, MVs contain significantly higher levels of DNA than ABs or EXOs. During the window of implantation, MVs contain an eleven-fold higher level of mtDNA when compared to cells-of-origin within the receptive endometrium, which possesses a lower mtDNA content and displays the upregulated expression of mitophagy-related genes. Furthermore, we demonstrate the internalization of EV-derived mtDNA by trophoblast cells of murine embryos, which associated with a reduction in mitochondrial respiration and ATP production. These findings suggest that the maternal endometrium suffers a reduction in mtDNA content during the preconceptional period, that mtDNA becomes packaged into secreted EVs that the embryo uptakes, and that the transfer of mtDNA to the embryo within EVs occurs alongside the modulation of bioenergetics during implantation.
The transmission of DNA through extracellular vesicles (EVs) represents a novel genetic material transfer mechanism that may impact genome evolution and tumorigenesis. We aimed to investigate the potential for vertical mitochondrial (mt)DNA transmission within maternal endometrial EVs to the pre-implantation embryo and describe any effect on embryo bioenergetics. We discovered that the human endometrium secretes all three general subtypes of EV - apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXOs) - into the human endometrial fluid (EF) within the uterine cavity. EVs become uniformly secreted into the EF during the menstrual cycle, with the proportion of different EV populations remaining constant; however, MVs contain significantly higher levels of DNA than ABs or EXOs. During the window of implantation, MVs contain an eleven-fold higher level of mtDNA when compared to cells-of-origin within the receptive endometrium, which possesses a lower mtDNA content and displays the upregulated expression of mitophagy-related genes. Furthermore, we demonstrate the internalization of EV-derived mtDNA by trophoblast cells of murine embryos, which associated with a reduction in mitochondrial respiration and ATP production. These findings suggest that the maternal endometrium suffers a reduction in mtDNA content during the preconceptional period, that mtDNA becomes packaged into secreted EVs that the embryo uptakes, and that the transfer of mtDNA to the embryo within EVs occurs alongside the modulation of bioenergetics during implantation.
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