Extracellular vesicles as mediators of cell-cell communication during implantation

总结 在人类和啮齿动物中，随着胚胎植入的开始，子宫经历了一个戏剧性的激素- 依赖性转化形成蜕膜，蜕膜是一种基质来源的分泌组织， 怀孕早期的胎儿。分化的基质细胞，称为蜕膜细胞，负责 产生和分泌旁分泌因子，促进广泛血管网的形成， 支持植入和胚胎发育。滋养层细胞的正常增殖和分化 细胞，形成功能性胎盘的关键，也受到未知的母体因素的影响 由蜕膜细胞分泌。目前的挑战是要了解精确的机制， 关键的功能信号从蜕膜细胞传递到子宫内的其他细胞类型 环境，以支持成功建立怀孕。越来越多的证据表明， 细胞外囊泡（EV）在许多生理过程中携带细胞间通讯的介质， 流程.几种不同类型的货物，包括蛋白质，脂质和核酸，可以发现内 这些囊泡当电动汽车被一个电池脱落并被另一个电池吸收时，这些货物被转移到 受体细胞并改变它们的功能。有趣的是，我们最近观察到小鼠和人类子宫内膜 在体外蜕膜化过程中，基质细胞在培养基中分泌大量EV。质谱 揭示了蜕膜EV含有具有不同活性的各种蛋白质货物，事实上， 这些EV的内化改变了受体细胞的功能。这些发现使我们提出了 假设由蜕膜细胞分泌的EV介导细胞信号传导和各种细胞之间的通信， 子宫内的细胞类型，以支持早期妊娠。因此，蜕膜EV运输的缺陷和 分泌物会损害指导怀孕建立的关键过程，导致疾病， 不孕为了验证这一假设，我们提出了两个具体目标。AIM 1将通过以下方式解决这些机制： 子宫内膜间质细胞分泌的EV控制早孕期间的蜕膜血管生成。在 目的2：探讨子宫内膜蜕膜细胞分泌的EV对子宫内膜功能的影响。 滋养层细胞这些目标的成功完成将提供对分子生物学的更深入的理解。 确保子宫内膜分化和血管生成与胚胎生长协调的途径 在胚胎植入的进行阶段。

SUMMARY In humans and rodents, with the onset of embryo implantation, the uterus undergoes a dramatic hormone- dependent transformation to form the decidua, a stroma-derived secretory tissue that encases the growing fetus during early pregnancy. Differentiated stromal cells, known as decidual cells, are responsible for producing and secreting paracrine factors that promote the formation of an extensive vascular network that supports implantation and embryo development. Proper proliferation and differentiation of the trophoblast cells, critical for the formation of a functional placenta, is also influenced by yet unknown maternal factors secreted by the decidual cells. The current challenge is to understand the precise mechanisms by which critical functional signals are communicated from the decidual cells to other cell-types within the uterine environment to support successful establishment of pregnancy. A growing body of evidence indicates that extracellular vesicles (EVs) carry mediators of intercellular communication during many physiological processes. Several different types of cargo, including proteins, lipids, and nucleic acids can be found within these vesicles. As EVs are shed by one cell and taken up by another, these cargoes are transferred to the recipient cells and alter their functions. Interestingly, we recently observed that mouse and human endometrial stromal cells secrete abundant EVs in culture media during in vitro decidualization. Mass spectrometry revealed that the decidual EVs harbor various protein cargoes with diverse activities, and indeed, internalization of these EVs altered the function of recipient cells. These findings led us to forward the hypothesis that EVs secreted by the decidual cells mediate cell signaling and communication between various cell types within the uterus to support early pregnancy. Consequently, a defect in decidual EV trafficking and secretion will impair critical processes that guide the establishment of pregnancy, leading to diseases and infertility. To test this hypothesis, we have proposed two specific aims. AIM 1 will address the mechanisms by which EVs secreted by endometrial stromal cells control decidual angiogenesis during early pregnancy. In AIM 2, we will investigate the effects of EVs secreted from endometrial decidual cells on the functionality of trophoblast cells. Successful completion of these aims will provide deeper understanding of the molecular pathways that ensure coordination of the endometrial differentiation and angiogenesis with embryonic growth during progressive phases of embryo implantation.