Extracellular Vesicles Mediated Early Embryo-Maternal Interactions.
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ABSTRACT:
SUBMITTER: Bridi A
PROVIDER: S-EPMC7037557 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
Extracellular Vesicles Mediated Early Embryo-Maternal Interactions.
Bridi Alessandra A Perecin Felipe F Silveira Juliano Coelho da JCD
International journal of molecular sciences 20200210 3
Embryo-maternal crosstalk is an important event that involves many biological processes, which must occur perfectly for pregnancy success. This complex communication starts from the zygote stage within the oviduct and continues in the uterus up to the end of pregnancy. Small extracellular vesicles (EVs) are part of this communication and carry bioactive molecules such as proteins, lipids, mRNA, and miRNA. Small EVs are present in the oviductal and uterine fluid and have important functions durin ...[more]
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Project description:Introduction: The pivotal role of extracellular vesicles (EVs) in facilitating effective communication between the embryo and maternal cells during the preimplantation stage of pregnancy has been extensively explored. Nonetheless, inquiries persist regarding the alterations in EV cargo from endometrial cells under stress conditions and its potential to elicit specific stress responses in trophoblast cells. Thus, the aim of this study was to elucidate the involvement of EV miRNA miRNAs in transmitting stress signals from maternal cells to trophoblasts. Methods: The receptive endometrial epithelium analogue RL95-2 cells were subjected to stress induction with 200 µM CoCl2 for 24 h before EV isolation. JAr trophoblast spheroids, which serve as embryos, were subjected to treatment with stressed or unstressed EVs derived from RL95-2 cells for 24 h. Transcriptomic alterations in the treated JAr spheroids as well as in the untreated group, as a negative control, were investigated by mRNA sequencing. Furthermore, the changes in EV miRNAs were assessed by sequencing EV samples. Results: A comprehensive analysis comparing the miRNA profiles between stressed and unstressed EVs revealed significant changes in 25 miRNAs. Furthermore, transcriptomic analysis of JAr spheroids treated with stressed RL95-2EVs versus unstressed EVs or the untreated group demonstrated 6 and 27 differentially expressed genes, respectively. Pathway enrichment analysis showed that stressed EVs induce alterations in gene expression in trophoblast cells, which is partially mediated by EV microRNAs. Discussion: Our results suggest that EVs can transfer stress signals from endometrial cells to the embryo. These discoveries shed new light on the mechanism underlying implantation failures under stress conditions. Unraveling the role of EVs in transmitting stress signals, can extend our knowledge to pave the way for targeted interventions to manage stress-related implantation failures.
| S-EPMC11330882 | biostudies-literature
Project description:Extracellular vesicles (EVs) have emerged as key messengers in intercellular communications. However, the precise mechanisms of how recipient cells read EV messages are not clear. In this study, we investigated the roles of EV protein cargo, EV parent cell type, and recipient cell type in EV function using a human embryo implantation model. The JAr cell line served as an analog of human trophoblast cells, and EVs isolated from these cells were introduced into receptive endometrial epithelial cell analog RL95-2 cells to simulate EV-mediated embryo-maternal communication. Downregulation of Zinc-finger protein 81 (ZNF81) gene expression in RL95-2 cells in response to trophoblast EVs were used as a readout of JAr EV functionality. EVs from the non-trophoblastic cell line (HEK-293 cells) were used as a control to assess the specificity of trophoblast EV functionality in endometrial epithelial cells. Our results demonstrated that ZNF81 gene downregulation is a specific response of RL95-2 cells to JAr EVs, as HEK-293 cell EVs did not induce any gene expression changes. Furthermore, we conducted an analysis of the proteomic cargo profiles of JAr and HEK-293 cell EVs. Interestingly, JAr EVs exhibited a unique proteomic cargo profile compared to that of HEK EVs. Some of the proteins uniquely identified in JAr EVs are also known to play roles in embryo implantation. Moreover, JAr EVs were specifically enriched with important transcription factors that regulate ZNF81 gene expression. These findings contribute to our understanding of the specificity of EV functionality and cellular response in the context of embryo implantation.
2024-07-03 | PXD050024 | Pride
Project description:Synchronous communication between the developing embryo and the receptive endometrium is crucial for embryo implantation. Thus, uterine receptivity evaluation is vital in managing recurrent implantation failure (RIF). The potential roles of small extracellular vesicle (sEV) miRNAs in pregnancy have been widely studied. However, the systematic study of sEVs derived from endometrium and its cargos during the implantation stage have not yet been reported. In this study, we isolated endometrium-derived sEVs from the mouse endometrium on D2 (pre-receptive phase), D4 (receptive phase), and D5 (implantation) of pregnancy. Herein, we reveal that multivesicular bodies (MVBs) in the endometrium increase in number during the window of implantation (WOI). Moreover, our findings indicate that CD63, a well-known sEV marker, is expressed in the luminal and glandular epithelium of mouse endometrium. The sEV miRNA expression profiles indicated that miR-34c-5p, miR-210, miR-369-5p, miR-30b, and miR-582-5p are enriched during WOI. Further, we integrated the RIF's database analysis results and found out that miR-34c-5p regulates growth arrest specific 1 (GAS1) for normal embryo implantation. Notably, miR-34c-5p is downregulated during implantation but upregulated in sEVs. An implication of this is the possibility that sEVs miR-34c-5p could be used to evaluate uterine states. In conclusion, these findings suggest that the endometrium derived-sEV miRNAs are potential biomarkers in determining the appropriate period for embryo implantation. This study also has several important implications for future practice, including therapy of infertility.
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| S-EPMC10752591 | biostudies-literature
Project description:Extracellular vesicles or exosomes are membrane encapsulated biological nanometric particles secreted virtually by all types of cells throughout the animal kingdom. They carry a cargo of active molecules to proximal and distal cells of the body as mechanism of physiological communication, to maintain natural homeostasis as well as pathological responses. Exosomes carry a tremendous potential for liquid biopsy and therapeutic applications. Thus, there is a global demand for simple and robust exosome isolation methods amenable to point-of-care diagnosis and quality control of therapeutic exosome manufacturing. This can be achieved by molecular profiling of the exosomes for use with specific sets of molecular-markers for diagnosis and quality control. Liquid biopsy is undoubtedly the most promising diagnosis process to advance "personalized medicine." Currently, liquid biopsy is based on circulating cancer cells, cell free-DNA, or exosomes. Exosomes potentially provide promise for early-stage diagnostic possibility; in order to facilitate superior diagnosis and isolation of exosomes, a novel platform is developed to detect and capture them, based on localized surface plasmon resonance (LSPR) of gold nanoislands, through strong affinity between exosomes and peptide called Venceremin or Vn96. Physical modeling, based on the characteristics of the gold nanoislands and the bioentities involved in the sensing, is also developed to determine the detection capability of the platform, which is optimized experimentally at each stage. Preliminary results and modeling present a relationship between the plasmonic shift and the concentration of exosomes and, essentially, indicate possibilities for label-free early diagnosis.
| S-EPMC6750071 | biostudies-literature
Project description:BackgroundThe period of time when the embryo and the endometrium undergo significant morphological alterations to facilitate a successful implantation-known as "window of implantation"-is a critical moment in human reproduction. Embryo and the endometrium communicate extensively during this period, and lipid bilayer bound nanoscale extracellular vesicles (EVs) are purported to be integral to this communication.MethodsTo investigate the nature of the EV-mediated embryo-maternal communication, we have supplemented trophoblast analogue spheroid (JAr) derived EVs to an endometrial analogue (RL 95-2) cell layer and characterized the transcriptomic alterations using RNA sequencing. EVs derived from non-trophoblast cells (HEK293) were used as a negative control. The cargo of the EVs were also investigated through mRNA and miRNA sequencing.ResultsTrophoblast spheroid derived EVs induced drastic transcriptomic alterations in the endometrial cells while the non-trophoblast cell derived EVs failed to induce such changes demonstrating functional specificity in terms of EV origin. Through gene set enrichment analysis (GSEA), we found that the response in endometrial cells was focused on extracellular matrix remodelling and G protein-coupled receptors' signalling, both of which are of known functional relevance to endometrial receptivity. Approximately 9% of genes downregulated in endometrial cells were high-confidence predicted targets of miRNAs detected exclusively in trophoblast analogue-derived EVs, suggesting that only a small proportion of reduced expression in endometrial cells can be attributed directly to gene silencing by miRNAs carried as cargo in the EVs.ConclusionOur study reveals that trophoblast derived EVs have the ability to modify the endometrial gene expression, potentially with functional importance for embryo-maternal communication during implantation, although the exact underlying signalling mechanisms remain to be elucidated.
| S-EPMC8293585 | biostudies-literature
Project description:To evaluate the effect of conditioned media (CM) and Extracellular Vesicles (EVs) derived from bovine oviduct epithelial cell (BOEC) lines on the developmental capacity of bovine zygotes and the quality of embryos produced in vitro, presumptive zygotes were cultured under specific conditions. In experiment 1, zygotes were cultured either on monolayers from BOEC extended culture (E), together with fresh BOEC suspension cells, or with BOEC-CM from fresh or E-monolayers. In experiment 2, EVs were isolated from BOEC-CM and characterized (150-200 nm) by Nanosight® and electron microscopy. Zygotes were cultured in the presence of 3x10(5) EVs/mL, 1.5x10(5) EVs/mL or 7.5x10(4) EVs/mL of fresh or frozen BOEC-EVs. In experiment 3, zygotes were cultured in absence of FCS but with EVs from BOEC-E that had been cultured in different culture media. In experiment 4, zygotes were cultured in SOF+5% normal-FCS, or EV-depleted-FCS. In all cases, cleavage rate (Day 2) and blastocyst development (Day 7-9) was assessed. Blastocysts on Days 7/8 were used for quality evaluation through differential cell count, cryotolerance and gene expression patterns. No differences were found among all FCS-containing groups in cleavage rate or blastocyst yield. However, embryos derived from BOEC-CM had more trophectoderm cells, while embryos derived from BOEC-EVs, both fresh and frozen, has more trophectoderm and total cells. More embryos survived vitrification in the BOEC-CM and BOEC-EV groups. In contrast, more embryos survived in the EV-depleted-FCS than in normal-FCS group. Gene expression patterns were modified for PAG1 for embryos cultured with EVs in the presence of FCS and for IFN-T, PLAC8, PAG1, CX43, and GAPDH in the absence of FCS. In conclusion, EVs from FCS have a deleterious effect on embryo quality. BOEC-CM and EVs during in vitro culture had a positive effect on the quality of in vitro produced bovine embryos, suggesting that EVs have functional communication between the oviduct and the embryo in the early stages of development.
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Project description:Most pregnancy losses worldwide are caused by implantation failure for which there is a lack of effective therapeutics. Extracellular vesicles are considered potential endogenous nanomedicines because of their unique biological functions. However, the limited supply of ULF-EVs prevents their development and application in infertility diseases such as implantation failure. In this study, pigs were used as a human biomedical model, and ULF-EVs were isolated from the uterine luminal. We comprehensively characterized the proteins enriched in ULF-EVs and revealed their biological functions in promoting embryo implantation. By exogenously supplying ULF-EVs, we demonstrated that ULF-EVs improve embryo implantation, suggesting that ULF-EVs are a potential nanomaterial to treat implantation failure. Furthermore, we identified that MEP1B is important in improving embryo implantation by promoting trophoblast cell proliferation and migration. These results indicated that ULF-EVs can be a potential nanomaterial to improve embryo implantation.
| S-EPMC9990359 | biostudies-literature
Project description:BackgroundExtracellular vesicles (EVs) present in oviductal (OF) and uterine fluid (UF) have been shown to enhance bovine embryo quality during in vitro culture by reducing lipid contents and modulating lipid metabolism-related genes (LMGs), while also influencing cell proliferation, suggesting their involvement on the regulation of different biological pathways. The regulation of signaling pathways related to cell differentiation, proliferation, and metabolism is crucial for early embryo development and can determine the success or failure of the pregnancy. Bioactive molecules within EVs in maternal reproductive fluids, such as microRNAs (miRNAs), may contribute to this regulatory process as they modulate gene expression through post-transcriptional mechanisms.ResultsFrom the 20 differentially expressed miRNAs, 19 up-regulated in UF-EVs (bta-miR-134, bta-miR-151-3p, bta-miR-155, bta-miR-188, bta-miR-181b, bta-miR-181d, bta-miR-224, bta-miR-23b-3p, bta-miR-24-3p, bta-miR-27a-3p, bta-miR-29a, bta-miR-324, bta-miR-326, bta-miR-345-3p, bta-miR-410, bta-miR-652, bta-miR-677, bta-miR-873 and bta-miR-708) and one (bta-miR-148b) in OF-EVs. These miRNAs were predicted to modulate several pathways such as Wnt, Hippo, MAPK, and lipid metabolism and degradation. Differences in miRNAs found in OF-EVs from the early luteal phase and UF-EVs from mid-luteal phase may reflect different environments to meet the changing needs of the embryo. Additionally, miRNAs may be involved, particularly in the uterus, in the regulation of embryo lipid metabolism, immune system, and implantation. This study evaluated miRNA cargo in OF-EVs from the early luteal phase and UF-EVs from the mid-luteal phase, coinciding with embryo transit within oviduct and uterus in vivo, and its possible influence on LMGs and signaling pathways crucial for early embryo development. A total of 333 miRNAs were detected, with 11 exclusive to OF, 59 to UF, and 263 were common between both groups.ConclusionsOur study suggests that miRNAs within OF- and UF-EVs could modulate bovine embryo development and quality, providing insights into the intricate maternal-embryonic communication that might be involved in modulating lipid metabolism, immune response, and implantation during early pregnancy.
| S-EPMC10993494 | biostudies-literature
Project description:The seminal plasma (sp), especially the extracellular vesicles of seminal plasma (sEV) which change with age can affect the endometrial immune microenvironment of female mice. However, it is unclear whether the decline in fertility of reproductively old males is related to the alterations of the sp and sEV which may have compromised effect on the immune microenvironment of the female uterus. In this research, we found a decrease in the implantation rate of pseudo-pregnant female mice which was treated with sp from reproductively old male mice (aged-sp group) than sp from young male mice (young-sp group). RNA-sequence analysis revealed an increase in the expression level of local cytokines and chemokines in the uterus of aged-sp groups than those of young-sp groups. Further in vitro experiments found an induction of dendritic cells (DC) maturation in the aged-sp groups. After isolating and characterizing sEV in young and aged male mice, we perfused the uterus of aged-sp group with sEV from young male mice and found it could partially rescue the low implantation rate of the aged-sp group. Further in vitro experiments found an induction of DC maturation after treating with sEV from aged male mice than that from young male mice, which indicated an age-related activation effect of sp and sEV. In conclusion, we found sp and sEV from aged male mice could induce the maturation of DC, which compromised the microenvironment of female reproductive tract, therefore leading to a decrease in implantation rate.
2021-07-27 | GSE180444 | GEO