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

围孕期的细胞应激，包括辅助生殖治疗(ART)引起的应激，可导致早期妊娠丢失、妊娠或出生体重降低以及出生后生长发育改变，造成短期(神经发育迟缓)和长期(心血管和代谢性疾病)的健康后果。我们以前的工作表明，胚胎滋养层和母体子宫内膜之间的第一次直接细胞相互作用发生在着床时，需要激活滋养层基因网络来启动侵袭和胎盘发育。这表明着床早期的事件对胎盘形成至关重要，也是妊娠后期胎儿对氧气/营养的需求能否得到满足的关键决定因素。在这里，我们将使用尖端的人类植入体外模型(人类胚胎、滋养层干细胞和子宫内膜器质)来检查已知的应激反应途径-GlcN酰化-一种改变蛋白质功能的翻译后修饰对植入的影响。我们建议表征滋养层干细胞对增强的GlcN酰化的反应，以及这种应激如何影响建立胎盘所需的滋养层细胞系的产生。我们将通过在促进或抑制细胞-细胞相互作用的条件下，在子宫内膜器官内共培养胚胎或胚胎模拟物(滋养层干细胞的球体)，来确定这些反应是如何受到母体线索的影响的。转录和表型数据集的生物信息学集成将揭示人类植入最早阶段出现的滋养层细胞群，并确定不利环境如何影响滋养层细胞谱系分配的平衡，从而对胎儿发育产生下游影响。对胎盘发育的最早步骤进行3D体外建模代表了该领域的一项重大方法学进步。有关人类胚泡发育和应激对干细胞群体的影响的信息将为人类胚胎发育能力和健康提供有价值的反馈。因此，与ART相关的行业将受益于有助于改进胚胎培养和冷冻保存的知识。我们开发新的围产期干预措施的工作最终将产生影响，减少胎儿/儿童死亡率和发病率，减轻与产科/新生儿护理和慢性成人疾病管理相关的经济和社会负担。

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.