Komsky-Elbaz Alisa, Shuhmaher Margarita, Sanchez-Lopez Javier Arturo, Teena Oria, Waiger Daniel, Zelinger Einat, Kossovsky Tally, Otikovs Leilah, Dilevsky Eshel, Soen Yoav, Hefetz Amir, Heifetz Yael
Department of Entomology, The Hebrew University, Rehovot, Israel.
Current Address: Biomedical Engineering, Technion Israel Institute of Technology, Haifa, Israel.
J Extracell Vesicles. 2025 Nov;14(11):e70161. doi: 10.1002/jev2.70161.
Intercellular communication is essential for healthy embryo development, yet the role and dynamics of extracellular space in the maternal-embryonic dialogue remain unclear. Furthermore, little is known of maternal and embryonic metabolic states during early endometrial preparation and after the embryo enters the uterine cavity. Using a human in vitro co-culture model and extracellular vesicle (EV)-specific tools, we dynamically tracked EV secretion, uptake and processing between embryonic and endometrial cells at early stages of cell-to-cell communication. Hormonal stimulation altered endometrial secretory output, producing distinct EV populations. Stimulated EVs (St-EVs) differed from non-stimulated EVs (NSt-EVs) in size, secretion dynamics, uptake efficiency and metabolic cargo, selectively packaging energy-related metabolites and aryl hydrocarbon receptor (AhR) ligands. AhR inhibition increased spheroid attachment, suggesting that AhR signalling regulates implantation by modulating the endometrial environment. Additionally, lipid droplets (LDs) affected by endometrial- and embryo-derived EVs were actively secreted and taken up by embryonic cells, highlighting their role in implantation. EVs were not only exchanged between the embryo and endometrium but were also rapidly internalized, influencing mitochondrial activity, lipid metabolism and extracellular matrix remodelling. Translation of EV-derived mRNA occurred within 1 h of uptake, driving cellular changes and enhancing embryo attachment. These findings suggest EVs, extracellular metabolites and LDs mobilized between the endometrium and embryo coordinate to promote embryo attachment and implantation. This study advances our understanding of embryo-maternal EV-mediated communication and provides a valuable model for investigating EV-mediated simultaneous intercellular bidirectional crosstalk in other biological contexts.
细胞间通讯对于胚胎的健康发育至关重要，然而细胞外空间在母胎对话中的作用和动态变化仍不清楚。此外，对于早期子宫内膜准备阶段以及胚胎进入子宫腔后母体和胚胎的代谢状态，我们了解甚少。利用人类体外共培养模型和细胞外囊泡（EV）特异性工具，我们在细胞间通讯的早期阶段动态追踪了胚胎细胞和子宫内膜细胞之间EV的分泌、摄取和加工过程。激素刺激改变了子宫内膜的分泌产物，产生了不同的EV群体。刺激后的EV（St-EV）在大小、分泌动态、摄取效率和代谢货物方面与未刺激的EV（NSt-EV）不同，它们选择性地包装与能量相关的代谢物和芳烃受体（AhR）配体。AhR抑制增加了球体附着，表明AhR信号通过调节子宫内膜环境来调控着床。此外，受子宫内膜和胚胎来源的EV影响的脂滴（LD）被胚胎细胞主动分泌和摄取，突出了它们在着床中的作用。EV不仅在胚胎和子宫内膜之间交换，还迅速被内化，影响线粒体活性、脂质代谢和细胞外基质重塑。EV衍生的mRNA在摄取后1小时内发生翻译，驱动细胞变化并增强胚胎附着。这些发现表明，在子宫内膜和胚胎之间调动的EV、细胞外代谢物和LD相互协作，促进胚胎附着和着床。这项研究增进了我们对胚胎-母体EV介导通讯的理解，并为研究其他生物学背景下EV介导的细胞间同时双向串扰提供了一个有价值的模型。
