Do interactions between endometrial derived extracellular vesicles and the microbiome mediate an optimal uterine environment?

为了在人类和牲畜中成功怀孕，子宫内膜（子宫内膜）必须为植入胚胎创造合适的环境。这种环境是由子宫内膜腺分泌物产生的，其中包括细胞外囊泡（ECV）：含有微小RNA和蛋白质的膜结合囊泡，这些微小RNA和蛋白质被靶细胞吸收以改变其功能。利用新的三维超微结构成像方法，我们发现ECVs形成于子宫内膜腺微绒毛上。我们现在需要了解子宫内膜ECV的形成和组成是如何调节的。子宫环境具有独特的微生物组，其与子宫内膜细胞相互作用，并被认为调节子宫内膜功能和容受性，但其机制尚不清楚。这种微生物群的改变或某些微生物群的存在可能会影响受精和着床，导致不良的妊娠结局。因此，我们需要确定微生物群及其产生的物质的存在是否会影响子宫内膜ECV的产生，无论是病理效应还是保护性反应。项目计划：1）研究子宫内膜ECV，包括其形成，microRNA含量，并确定这些变化是否响应于微生物的存在和产生的物质。2）确定子宫内膜ECV是否与子宫内膜微生物组内的细菌细胞相互作用。3）为了确定子宫内膜微生物组（来自组织和液体样本）是否与子宫内膜表型相关，在南安普顿建立了子宫内膜腺体分离和3D成像方法。这些团队在ECV、mRNA和microRNA-seq的分离方面具有专业知识，在生物信息学分析方面具有专业知识。我们定期收集来自一系列生育表型的人类子宫内膜组织和体液样本。这项工作的影响将来自于对ECV生理作用及其调节的更好理解，再加上这些发现的应用，以提高人类和牲畜育种计划中自然和辅助受孕的成功率。

For successful pregnancy in humans and livestock, the endometrium (the lining of the womb) must create the right environment for the implanting embryo. This environment is created by endometrial gland secretions, which include extracellular vesicles (ECVs): membrane bound vesicles containing microRNA and proteins that are taken up by target cells to change their function. Using novel 3D ultrastructural imaging approaches, we show that ECVs form on endometrial gland microvilli. We now need to understand how the formation and composition of endometrial ECVs are regulated. The uterine environment has a unique microbiome that interacts with the endometrial cells and is thought to modulate endometrial function and receptivity, however the mechanisms are unclear. Alteration of this microbiota or presence of certain microbiota may effect fertilization and implantation, leading to poor pregnancy outcome.We therefore need to establish whether the presence of the microbiome and substances it produces can influence the endometrial production of ECVs, be it a pathological effect or a protective response.Project plan:1) To characterise endometrial ECVs including their formation, microRNA content and establish whether these change in response to microbial presence and produced substances.2) To establish whether endometrial ECVs interact with bacterial cells within the endometrial microbiome.3) To determine whether the endometrial microbiome (from tissue and fluid samples) relates to endometrial phenotypes.Endometrial gland isolation and 3D imaging approaches are established in Southampton. The teams have expertise in isolation of ECVs, mRNA and microRNA-seq and expertise in bioinformatic analyses.We routinely collect human endometrial tissue and fluid samples from a range of fertility phenotypes.The impact of this work will come from improved understanding of the physiological role of ECVs and their regulation, plus the application of these findings to improve the success of natural and assisted conception in humans and livestock breeding programs.