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Uterine luminal-derived extracellular vesicles: potential nanomaterials to improve embryo implantation.

ABSTRACT: 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.

SUBMITTER: Hong L

PROVIDER: S-EPMC9990359 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Uterine luminal-derived extracellular vesicles: potential nanomaterials to improve embryo implantation.

Hong Linjun L Zang Xupeng X Hu Qun Q He Yanjuan Y Xu Zhiqian Z Xie Yanshe Y Gu Ting T Yang Huaqiang H Yang Jie J Shi Junsong J Zheng Enqin E Huang Sixiu S Xu Zheng Z Liu Dewu D Cai Gengyuan G Li Zicong Z Wu Zhenfang Z

Journal of nanobiotechnology 20230307 1

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 comprehensi ...[more]

PMID: 36882792

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Project description:Purpose: Extracellular vescicles (EVs) of uterine origin have recently been identified, but they are not comprised by current diagnostics on endometrial receptivity. In order to test the possibility to use EVs as biomarker reservoirs for non-invasive monitoring of the endometrial status, we defined two experimental designs: in step a) we aimed at assessing the concordance between the transcriptome of endometrial tissue and uterine fluid-derived EVs (UF-EVs); in step b) we aimed at unraveling the transcriptomic profile of UF-EVs released during the receptive phase and associated with successful implantation Methods: RNAseq analysis was performed on total RNA isolated from a) endometrial biopsies and UF-EVs concomitantly collected from regularly cycling women; b) UF-EVs collected in the pre-receptive (LH+2) versus the receptive (LH+7) phase of provenly fertile women and in the receptive phase (LH+7) of women undergoing assisted reproduction and transfer of an euploid blastocyst. In the latter group, the outcomes of the following embryo transfer attempt were recorded, in order to compare the transcriptomic profile of women with successful versus failed implantation. Differential Gene Expression (DGE) and Gene Set Enrichment (GSEA) analyses were performed. Results: In the first experimental design, a highly significant correlation was found between the transcriptional profiles of endometrial tissue biopsies and corresponding UF-EVs (r=0.71 p<0.001; ρ=0.65 p<0.001). In the second experimental design, using a large group of 73 samples, 16,777 genes were overall found to be expressed in UF-EVs. Of these, DGE analysis showed that 942 were up-regulated and 1,305 down-regulated during the receptive phase in women with proven fertility and 97 were up-regulated and 64 down-regulated during the receptive phase of women achieving successful implantation versus women failing to achieve pregnancy in the subsequent cycle. 41 genes had a statistically significant different expression in both comparisons. We additionally tested wether transcripts used by current endometrial receptivity tests based on endometrial biopsies (Endometrial Receptivity Assay, ERA test) could also be detected in UF-EVs: out of 238 ERA test gene data-set, GSEA highlighted 219 genes with similar transcriptional profile in UF-EVs. We then performed another comparison adding the list of genes consisting of the ‘metasignature’ transcriptome derived from the published meta-analysis of endometrial receptivity associated transcripts, comprising 57 genes. This last intersection identified 38 genes expressed in UF-EVs that i) show differential expression with the same transcriptional profile (same trends) in both EVs and ERA test assay; ii) belong to the leading edge of genes with the most significant enrichment score in our analysis; iii) are identified as receptivity-associated genes by the current meta-analysis on endometrial transcriptome. Conclusions: This is the first study showing the capacity of UF-EVs to reflect the endometrial tissue transcriptional status and to establish a signature of genes expressed in UF-EVs that might serve as putative biomarkers for non-invasive endometrial receptivity tests.

Dataset Information

Uterine luminal-derived extracellular vesicles: potential nanomaterials to improve embryo implantation.

Publications

Uterine luminal-derived extracellular vesicles: potential nanomaterials to improve embryo implantation.

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