Department of Molecular and Integrative Physiology, University of Illinois, Urbana- Champaign, Urbana, IL 61801.
Department of Comparative Biosciences, University of Illinois, Urbana-Champaign, Urbana, IL 61802.
Proc Natl Acad Sci U S A. 2022 Sep 20;119(38):e2200252119. doi: 10.1073/pnas.2200252119. Epub 2022 Sep 12.
In humans, the uterus undergoes a dramatic transformation to form an endometrial stroma-derived secretory tissue, termed decidua, during early pregnancy. The decidua secretes various factors that act in an autocrine/paracrine manner to promote stromal differentiation, facilitate maternal angiogenesis, and influence trophoblast differentiation and development, which are critical for the formation of a functional placenta. Here, we investigated the mechanisms by which decidual cells communicate with each other and with other cell types within the uterine milieu. We discovered that primary human endometrial stromal cells (HESCs) secrete extracellular vesicles (EVs) during decidualization and that this process is controlled by a conserved HIF2α-RAB27B pathway. Mass spectrometry revealed that the decidual EVs harbor a variety of protein cargo, including cell signaling molecules, growth modulators, metabolic regulators, and factors controlling endothelial cell expansion and remodeling. We tested the hypothesis that EVs secreted by the decidual cells mediate functional communications between various cell types within the uterus. We demonstrated that the internalization of EVs, specifically those carrying the glucose transporter 1 (GLUT1), promotes glucose uptake in recipient HESCs, supporting and advancing the decidualization program. Additionally, delivery of HESC-derived EVs into human endothelial cells stimulated their proliferation and led to enhanced vascular network formation. Strikingly, stromal EVs also promoted the differentiation of trophoblast stem cells into the extravillous trophoblast lineage. Collectively, these findings provide a deeper understanding of the pleiotropic roles played by EVs secreted by the decidual cells to ensure coordination of endometrial differentiation and angiogenesis with trophoblast function during the progressive phases of decidualization and placentation.
在人类中，子宫在早孕期间经历剧烈的转变，形成子宫内膜基质衍生的分泌组织，称为蜕膜。蜕膜分泌各种因子，以自分泌/旁分泌的方式作用，促进基质细胞分化，促进母体血管生成，并影响滋养层细胞分化和发育，这对功能性胎盘的形成至关重要。在这里，我们研究了蜕膜细胞之间以及与子宫环境中的其他细胞类型之间相互交流的机制。我们发现，原代人子宫内膜基质细胞（HESCs）在蜕膜化过程中分泌细胞外囊泡（EVs），这一过程受保守的 HIF2α-RAB27B 途径控制。质谱分析显示，蜕膜 EVs 携带多种蛋白 cargo，包括细胞信号分子、生长调节剂、代谢调节剂以及控制内皮细胞扩张和重塑的因子。我们测试了这样一个假设，即蜕膜细胞分泌的 EVs 介导子宫内各种细胞类型之间的功能通讯。我们证明了 EVs 的内化，特别是那些携带葡萄糖转运蛋白 1（GLUT1）的 EVs，促进了受者 HESCs 的葡萄糖摄取，支持并推进了蜕膜化程序。此外，将源自 HESC 的 EVs 递送到人内皮细胞中可刺激其增殖，并导致血管网络形成增强。引人注目的是，基质 EVs 还促进了滋养层干细胞向绒毛外滋养层谱系的分化。总的来说，这些发现深入了解了蜕膜细胞分泌的 EVs 所发挥的多效作用，以确保在蜕膜化和胎盘形成的渐进阶段，子宫内膜分化和血管生成与滋养层功能的协调。
