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.