Signaling pathways in mouse and human trophoblast differentiation: a comparative review

Abstract

The mouse is often used as a model for understanding human placentation and offers multiple advantages, including the ability to manipulate gene expression in specific compartments and to derive trophoblast stem cells, which can be maintained or differentiated in vitro. Nevertheless, there are numerous differences between the mouse and human placentas, only the least of which are structural. This review aims to compare mouse and human placentation, with a focus on signaling pathways involved in trophoblast lineage-specific differentiation.

Fig. 1

Mouse and human placenta. Although both mouse and human placentas are hemochorial, some structural differences can be observed. a Mouse placenta: the labyrinth is the functional structure where gas/nutrient exchange occurs. Maternal blood is separated from fetal blood by three layers of trophoblasts (SynT-I, SynT-II and sinusoidal giant cells). The supportive junctional zone contains spongiotrophoblast, which give rise to trophoblast giant cells (TGCs) and glycogen trophoblasts. Both TGCs and glycogen trophoblasts are only modestly invasive, compared to the human extravillous trophoblasts (EVTs). b Human placenta: the functional structure for gas/nutrient exchange is the chorionic villus. In the first trimester, maternal blood is separated from the fetal blood by two layers of trophoblast, the syncytiotrophoblast (STB) and the cytotrophoblast (CTB) stem cells. Later in gestation, the continuous CTB layer disappears and only sparse CTBs are visible at term. The EVTs arise from the trophoblast cell column, and are highly invasive, penetrating up to one-third of the thickness of the uterus. Endovascular EVTs extensively remodel maternal spiral arterioles to ensure correct blood supply to the growing embryo. c Table listing functionally and/or structurally analogous mouse and human trophoblast subtypes

Fig. 2

Timeline comparison of mouse and human placental development. Timeline for both species is calculated from conception, with assignment of day of observation of the copulation plug as E0.5 in the mouse, and mid-menstrual cycle (corresponding to time of ovulation followed by fertilization) as coitus in human. The formation of blastocyst defines two distinct populations of cells: the inner cell mass and the outer trophectoderm, at E3.5 in mouse and approximately day 5 post-coitum in human. Implantation occurs at E4.5 in mouse and day 7–8 post-coitum in human. In mouse, chorio-allantoic attachment starts off the formation of the labyrinth around E8.0, with branching morphogenesis complete by E10.5, the half point through gestation, although the labyrinth continues to grow in the latter half of gestation. In human, villous formation starts early, around day 13 post-coitum, and the villi are fully vascularized by the end of the first/beginning of the second trimester. However, further maturation of both the stroma and trophoblast continues through the second trimester. In mouse, the junctional zone and TGCs are also fully formed by E10.5, although glycogen cells continue to differentiate and invade the uterus along with specific TGC subtypes. In human, EVT invasion and remodeling of maternal spiral arterioles are complete by the end of the first trimester, at which point the chorionic villi become fully bathed in well-oxygenated maternal blood