Extracellular vesicles as mediators of cell-cell communication during implantation

细胞外囊泡作为植入过程中细胞间通讯的介质

基本信息

批准号：
10684030
负责人：
MILAN K BAGCHI
金额：
$ 18.99万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10684030
关键词：
Ablation Angiogenic Factor Beds Blood Vessels Botulinum Toxins Cell Communication Cell Differentiation process Cell secretion Cells Communication Cone Culture Media Decidua Decidual Cell Decidual Cell Reactions Defect Development Disease Embryo Embryonic Development Endometrial Endometrial Stromal Cell Endothelial Cells Endothelium Ensure Environment Family Fetus Genes Goals Growth Guanosine Triphosphate Phosphohydrolases Hormones Human Impairment In Vitro Infertility Laboratories Lipids Mass Spectrum Analysis Mediating Mediator Modeling Molecular Mus Nucleic Acids Pathway interactions Phase Phenotype Physiological Processes Placenta Play Pregnancy Process Proliferating Proteins Rodent Role Signal Pathway Signal Transduction Somatomedins Stromal Cells Testing Tissues Uterus Vesicle angiogenesis cell type early pregnancy exosome experimental study extracellular vesicles fetal fetal loss implantation in vivo insight intercellular communication member mouse model natural Blastocyst Implantation paracrine rac1 GTP-Binding Protein rho support network trafficking trophoblast trophoblast stem cell

项目摘要

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.

概括在人类和啮齿类动物中，随着胚胎着床的开始，子宫会经历一种戏剧性的激素- 依赖转化形成蜕膜，蜕膜是一种基质衍生的分泌组织，包裹着正在生长的细胞怀孕早期的胎儿。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，促进广泛血管网络的形成支持植入和胚胎发育。滋养层的正常增殖和分化对于形成功能性胎盘至关重要的细胞也受到未知母体因素的影响由蜕膜细胞分泌。当前的挑战是了解其精确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支持成功怀孕的环境。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。可以在其中找到几种不同类型的货物，包括蛋白质、脂质和核酸这些囊泡。当电动汽车被一个电池卸下并被另一个电池占用时，这些货物就会被转移到受体细胞并改变其功能。有趣的是，我们最近观察到小鼠和人类子宫内膜基质细胞在体外蜕膜化过程中在培养基中分泌丰富的EV。质谱分析研究表明，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。这些发现促使我们提出假设蜕膜细胞分泌的 EV 介导细胞信号传导和各种细胞之间的通讯子宫内的细胞类型支持早期妊娠。因此，蜕膜 EV 贩运的缺陷和分泌物会损害指导怀孕的关键过程，导致疾病和不孕症。为了检验这一假设，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：子宫内膜基质细胞分泌的 EV 控制妊娠早期蜕膜血管生成。在 AIM 2，我们将研究子宫内膜蜕膜细胞分泌的EV对子宫内膜蜕膜细胞功能的影响滋养层细胞。成功完成这些目标将加深对分子生物学的理解。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展阶段。