Characterisation of the Extracellular Vesicles Role in the Mediation of Embryo-Maternal Communication at the Time of Implantation

Abstract

The pregnancy rates after employing Assisted Reproductive Technologies (ART) treatments are relatively low. The most common cause of pregnancy failure appears to be impaired uterine receptivity and inefficient embryo-maternal communication. In recent years, membranous nanoparticles secreted from eukaryotic cells, known as Extracellular Vesicles (EVs), have been identified as essential mediators of intercellular communication and regulators of reproductive processes, including implantation. However, their role in embryo-endometrium communication during early implantation is not fully understood. This thesis investigates the role of EVs in bidirectional embryo-endometrial communication during early implantation, focusing on the impact of a non-receptive endometrium. An in vitro co-culture model, utilising 3D trophoblast spheroids and endometrial monolayers, simulated the dynamic interactions during implantation. The impact of EVs on embryo-maternal communication was investigated at both functional and transcriptomic levels, including the influence of endometrial EV miRNA cargo. Findings revealed a critical interplay between preimplantation embryo surrogates and the receptive endometrium. Receptive endometrial cells responded significantly to trophoblast EVs, and trophoblast spheroids responded uniquely to receptive endometrial EVs. These findings suggest that the receptive endometrium establishes an environment that actively supports embryo development and enhances implantation potential. Conversely, our findings highlighted the potential detrimental impact of a non-receptive endometrium. EVs from a non-receptive endometrium may impair early embryo development and function. Embryo-derived EVs may struggle to elicit a response from compromised endometrial cells. This disrupted communication may contribute to recurrent implantation failure, where inadequate endometrial receptivity and compromised embryo-maternal dialogue underlie repeated failures. In additional work, EVs derived from bovine milk were investigated as a potential natural source of EVs. Their role in enhancing trophoblast spheroid binding and the effect on the trophoblast transcriptome were evaluated, with a focus on milk EV miRNAs. The results demonstrated the promise of bovine milk EVs as a potential therapeutic avenue for improving implantation outcomes.