Department of Pathophysiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, Tartu University, Tartu, Estonia.
Institute of Veterinary Medicine and Animal Sciences, Estonian University of Life Sciences, Tartu, Estonia.
Reprod Biol Endocrinol. 2021 Jul 21;19(1):115. doi: 10.1186/s12958-021-00801-5.
The period of time when the embryo and the endometrium undergo significant morphological alterations to facilitate a successful implantation-known as "window of implantation"-is a critical moment in human reproduction. Embryo and the endometrium communicate extensively during this period, and lipid bilayer bound nanoscale extracellular vesicles (EVs) are purported to be integral to this communication.
To investigate the nature of the EV-mediated embryo-maternal communication, we have supplemented trophoblast analogue spheroid (JAr) derived EVs to an endometrial analogue (RL 95-2) cell layer and characterized the transcriptomic alterations using RNA sequencing. EVs derived from non-trophoblast cells (HEK293) were used as a negative control. The cargo of the EVs were also investigated through mRNA and miRNA sequencing.
Trophoblast spheroid derived EVs induced drastic transcriptomic alterations in the endometrial cells while the non-trophoblast cell derived EVs failed to induce such changes demonstrating functional specificity in terms of EV origin. Through gene set enrichment analysis (GSEA), we found that the response in endometrial cells was focused on extracellular matrix remodelling and G protein-coupled receptors' signalling, both of which are of known functional relevance to endometrial receptivity. Approximately 9% of genes downregulated in endometrial cells were high-confidence predicted targets of miRNAs detected exclusively in trophoblast analogue-derived EVs, suggesting that only a small proportion of reduced expression in endometrial cells can be attributed directly to gene silencing by miRNAs carried as cargo in the EVs.
Our study reveals that trophoblast derived EVs have the ability to modify the endometrial gene expression, potentially with functional importance for embryo-maternal communication during implantation, although the exact underlying signalling mechanisms remain to be elucidated.
胚胎和子宫内膜经历显著的形态改变以促进成功着床的时间段——即“着床窗口”——是人类生殖中的一个关键时期。在此期间，胚胎和子宫内膜广泛地进行交流，而双层脂膜结合的纳米级细胞外囊泡（EVs）被认为是这种交流的重要组成部分。
为了研究 EV 介导的胚胎-母体通讯的性质，我们向子宫内膜模拟物（RL 95-2）细胞层中补充滋养层模拟球体（JAr）衍生的 EVs，并使用 RNA 测序来描述转录组变化。非滋养层细胞（HEK293）衍生的 EV 用作阴性对照。还通过 mRNA 和 miRNA 测序研究了 EV 的货物。
滋养层球体衍生的 EVs 在子宫内膜细胞中引起了剧烈的转录组变化，而非滋养层细胞衍生的 EVs 未能引起这种变化，这证明了 EV 起源的功能特异性。通过基因集富集分析（GSEA），我们发现子宫内膜细胞中的反应集中在细胞外基质重塑和 G 蛋白偶联受体信号转导上，这两者都已知与子宫内膜容受性有关。在子宫内膜细胞中下调的约 9%的基因是仅在滋养层模拟物衍生的 EVs 中检测到的 miRNA 的高置信度预测靶标，这表明子宫内膜细胞中表达减少的只有一小部分可以直接归因于 miRNA 作为 EV 货物携带的基因沉默。
我们的研究表明，滋养层衍生的 EVs 具有改变子宫内膜基因表达的能力，这可能对胚胎-母体通讯在着床期间具有功能重要性，尽管确切的潜在信号机制仍有待阐明。
