Deciphering the maternal uterine signals that shape placenta development.

In brief: Proper placental development depends not only on fetal trophoblast signaling but also on critical maternal uterine signals. This review highlights how decidual factors and maternal-fetal crosstalk regulate trophoblast invasion and placentation. Abstract: In humans and rodents, proper formation of a hemochorial placenta is essential for a successful pregnancy, as the placenta serves as the maternal-fetal interface that facilitates the exchange of nutrients, gases, and waste between the mother and the developing fetus. The fetal compartment of the placenta is formed by extraembryonic trophoblast cells that proliferate and differentiate into distinct lineages that play specialized roles during placental development. Trophoblast lineage development and function are highly dependent upon embryonic paracrine signaling and timely activation of transcription factors within the trophoblasts. However, recent studies have increasingly emphasized the critical role of maternal factors in regulating trophoblast differentiation and placental development. Notably, conditional knockout mouse models have demonstrated the essential contribution of maternal decidual expression of specific molecular signals in orchestrating these processes. In this review, we summarize the role of maternal uterine signals in shaping placental development. We examine the role of decidua-derived secreted factors in directing trophoblast lineage specification and promoting appropriate levels of trophoblast invasion. Additionally, we explore the crosstalk between maternal- and fetal-derived signals that collectively regulate the extent and timing of trophoblast invasion into the uterine tissue. The interplay between maternal immune cells and trophoblasts is also discussed, with a focus on mechanisms that not only support immune tolerance to the semi-allogeneic placenta but also mediate trophoblast invasion and vascular remodeling. Finally, we consider the clinical implications of maternal influences on placentation, including the emerging potential of decidual extracellular vesicles as non-invasive biomarkers for pregnancy health and placental dysfunction.