Extracellular vesicles as mediators of cell-cell communication during implantation

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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.