Peri-conceptional stress signalling through O-GlcNAcylation: effects on the early maternal-embryonic interface

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Cellular stress during the peri-conceptional period, including that caused by assisted reproductive treatment (ART), can lead to early pregnancy loss, reduced gestation or birthweight and altered postnatal growth, with short- (neurodevelopmental delay) and long- (cardiovascular and metabolic disease)-term health consequences. Our previous work shows that the first direct cellular interaction between embryonic trophectoderm and the maternal endometrium, which occurs at implantation, is needed to activate the trophoblast gene networks that initiate invasion and placental development. This indicates that events at early implantation are critically important for placentation and a key determinant of whether fetal demand for oxygen/nutrients can be met later in pregnancy. Here we will use cutting-edge in vitro models of human implantation (human embryos, trophoblast stem cells and endometrial organoids) to examine the effects of a known stress response pathway - GlcNAcylation, a post-translational modification that alters protein function - on implantation.We propose to characterise trophoblast stem cell response to enhanced GlcNAcylation and how such stress affects the generation of trophoblast cell lineages required to build a placenta. We will determine how these responses are influenced by maternal cues by co-culturing embryos or embryo mimics (spheroids of trophoblast stem cells) inside endometrial organoids under conditions that promote or suppress cell-cell interactions. Bioinformatic integration of transcriptomic and phenotypic datasets will reveal the trophoblast cell populations that emerge at the earliest phase of human implantation and determine how an adverse environment affects the balance of trophoblast lineage allocation leading to downstream impacts on fetal development. Modelling the earliest steps of placental development in 3D in vitro represents a significant methodological advance for the field. Information on human blastocyst development and the impact of stress on stem cell populations will provide valuable feedback on human embryo developmental competence and health. Thus industries associated with ART will benefit from knowledge that will facilitate improvements to embryo culture and cryopreservation. Our work towards the development of novel peri-conceptional interventions will ultimately have impact by reducing fetal/child mortality and morbidity and relieving the economic and societal burden associated with obstetric/neonatal care and the management of chronic adult disease.