Signalling molecules that mediate preimplantation embryo development and implantation

© 2021 Kathryn Helen GurnerImplantation of the blastocyst into the endometrium is a critical process for reproduction and the establishment of successful pregnancy. However, approximately 30% of natural pregnancies are lost in the peri-implantation period, and this is compounded in the 1 in 6 couples worldwide that experience infertility. Hence, failure of implantation is a major limitation of reproductive success. The success of human implantation and pregnancy is dependent on the presence of an appropriately developed blastocyst, a receptive endometrium and a dynamic dialogue between these tissues, mediated by signalling molecules of both maternal and embryonic origin. This is highlighted by the fact that both poor embryo quality, and inadequate endometrial receptivity are major contributing factors to poor implantation. Therefore, it is evidently necessary to optimise both embryo quality and viability following in vitro culture, as well as increase our understanding of the regulation of endometrial receptivity and implantation to improve pregnancy success in both natural and assisted pregnancies Using a mouse model, the effects of supplementing a defined group of maternal growth factors (GFs) and cytokines (GF5) to embryo culture media as a potential method to improve embryonic quality following in vitro culture was investigated. GF5 improved morphological indicators of embryonic development and viability, however these changes were associated with parallel alterations to the transcriptome relative to in vivo derived embryonic counterparts, thus highlighting the importance of cooperative actions between growth promoting and growth inhibiting factors within the in vivo environment to facilitate normal embryonic development and programming. The use of GFs and cytokines as clinical medium supplements to promote embryo development was further investigated through the development of a novel method by which GFs could be stabilised and subsequently delivered to the in vitro embryo, an approach that negates the breakdown of GFs associated with storage in solution. Investigations into the role of embryonic signals in facilitating implantation demonstrated a role for lactate as an embryonic signal to promote functional remodelling of the endometrium for receptivity and implantation. Lactate was found to downregulate proliferation and cell polarity within the luminal epithelium, as well altering stromal migratory capacity and promoting angiogenic induction at the implantation site. Further examination of a functional effect of lactate in other reproductive tissues failed to identify a role for lactate in the regulation of cumulus cell expansion, transcriptional regulation of a subset of genes involved in lactate transport or metabolism, or sperm motility characteristics, despite the identification of GPR81 in each of these cell types. Overall, the research presented in this thesis enhances our understanding of maternal-fetal interactions within the in vivo environment and demonstrates the capacity of both the embryo and the endometrium to modulate several cellular functions to promote optimal embryonic development and the initiation of implantation. Together, these studies contribute to our understanding and ability to improve the quality of embryos produced through in vitro culture, as well as increase our understanding of the regulation of endometrial receptivity, which together, should help to augment the success of both natural and assisted pregnancies