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Can human embryo-released extracellular vesicles govern endometrial receptivity and inform on vanguard embryo diagnostics and fertility therapeutics?

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Embryo-secreted vesicles can predict the outcome of implantation

Embryos with abnormal chromosomes account for approximately 50 % of in vitro fertilisation (IVF) failed attempts. European scientists have discovered biomarkers for screening the genetic integrity of embryos in a non-invasive manner prior to implantation.

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Preimplantation genetic testing (PGT) is an early form of prenatal genetic diagnosis of aneuploid embryos that do not have the correct number of chromosomes. Although PGT aims to increase implantation potential by selecting only genetically normal embryos, it requires an invasive biopsy of the embryo cells that may decrease embryo quality. Therefore, there is an imminent need for safer, non-invasive methods in IVF practice to screen preimplantation embryos.

Biomarkers based on embryo-secreted extracellular vesicles

To address this problem, the CERVINO initiative, which was undertaken with the support of the Marie Skłodowska-Curie Actions (MSCA) programme, discovered non-invasive biomarkers based on extracellular vesicles (EVs). Secreted by most cells, EVs carry diverse bioactive cargo as a means of intercellular communication. Their participation in the maintenance of normal and pathophysiological conditions, including cancer, neurodegenerative diseases and infectious diseases, is emerging. As the project supervisor Paola Viganò explains: “EVs have attracted significant attention in the pathophysiology of reproduction due to their participation in the crosstalk between the embryo and the endometrium.” Previous work by the CERVINO scientists has shown that IVF embryos release EVs that can be transferred to the cells lining the womb and alter their behaviour. Moreover, a number of studies in animal models have indicated that the number of secreted EVs is proportional to the embryo competence for implantation. In CERVINO, comparison of the EV cargo between normal and aneuploid embryos indicated that the latter enclose four RNA fragments in higher abundance than normal embryos. Scientists revealed that when womb cells internalised the EVs from aneuploid embryos, they overexpressed a particular molecule that prohibited implantation. “Therefore, it is possible that aneuploid embryos are rejected via a mechanism whereby EVs deliver a rejection signal to the womb,” emphasises the MSCA research fellow Sofia Makieva.

CERVINO findings open the door to non-invasive PGT

Infertility affects approximately 10 % of European couples, the majority of which turn to IVF treatments. Half of failed IVF attempts are caused by aneuploid embryos, and the rest are attributed to unexplained causes. Therefore, it is critical to understand what biological mechanisms affect the successful attachment of embryos to the womb lining to better manage couples suffering from recurrent IVF implantation failure. The CERVINO findings underscore a role for EV cargo in the crosstalk between the embryo and the endometrium. The upregulation of some molecules in endometrial cells following reception of EVs from aneuploid embryos proposes a new mechanism underlying implantation failure where the embryos themselves stimulate a rejection response in the womb. The CERVINO discovery that the RNA cargo of EVs secreted from aneuploid embryos differs from that of genetically normal embryos potentiates the development of a non-invasive PGT methodology. Presently, access to PGT is rising, but embryo biopsy compromises embryo quality and its long-term safety in humans has yet to be fully evaluated. Moreover, a number of clinics include PGT as an integral part of IVF procedures to ensure embryo genetic integrity. This, however, significantly increases the overall cost of IVF, making it expensive for many couples. A non-invasive embryo screening method based on the analysis of embryo-secreted EVs would reduce the cost and make IVF treatment more successful.

Keywords

CERVINO, EV, IVF, aneuploid embryo, PGT, womb, extracellular vesicle, in vitro fertilisation, preimplantation genetic testing

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