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：
10509594
负责人：
MILAN K BAGCHI
金额：
$ 22.95万
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/10509594
关键词：
Ablation Address Angiogenic Factor Beds Blood Vessels Cell Communication Cell Differentiation process 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 of activation protein Modeling Molecular Mus Nucleic Acids Pathway interactions Phase Phenotype Physiological Processes Placenta Play Pregnancy Process 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.

概括在人类和啮齿动物中，随着胚胎植入的开始，子宫经历了戏剧性的激素 - 依赖转化形成decidua，decidua是一种构造了构造增长的基质衍生的分泌组织怀孕初期的胎儿。分化的基质细胞（称为candual细胞）负责产生和分泌旁分泌因素，促进形成广泛的血管网络支持植入和胚胎开发。适当的滋养细胞增殖和分化细胞对于形成功能性胎盘的重要性也受母亲因素但未知的影响由dec骨细胞分泌。当前的挑战是了解确切的机制关键的功能信号从结单细胞传达到子宫内的其他细胞类型支持成功建立怀孕的环境。越来越多的证据表明细胞外囊泡（EV）在许多生理学期间携带细胞间通讯的介体过程。可以在内发现几种不同类型的货物，包括蛋白质，脂质和核酸这些囊泡。由于电动汽车被一个牢房脱离并被另一个单元吸收，这些货物被转移到受体单元格并改变其功能。有趣的是，我们最近观察到小鼠和人子宫内膜基质细胞在体外deDialatiatization期间分泌培养基中丰富的EV。质谱法揭示了decidual evs拥有各种活动的各种蛋白质货物，甚至这些电动汽车的内在化改变了受体细胞的功能。这些发现使我们转发了由candual细胞分泌的EV介导细胞信号传导和各种之间的通信的假设子宫内的细胞类型支持早期妊娠。因此，decidual ev贩运的缺陷和分泌物会损害指导妊娠的关键过程，导致疾病，并不育。为了检验这一假设，我们提出了两个具体目标。 AIM 1将通过由子宫内膜基质细胞分泌的EV控制妊娠初期的否定性血管生成。在 AIM 2，我们将调查子宫内膜decIDual细胞分泌的电动汽车对滋养细胞细胞。这些目标的成功完成将为分子提供更深入的了解确保子宫内膜分化和血管生成协调的途径与胚胎生长在胚胎植入的进行性阶段。