Irusta, A. M. | bioRxiv Science

bioRxiv2025

PPARG directs trophoblast cell fate and establishment of the uterine-placental interface

The expansion and differentiation of trophoblast stem (TS) cells are critical for defining fundamental properties of the placenta. Specialized trophoblast cells exit the placenta and enter and transform the uterus, including restructuring uterine spiral arteries. In the human these cells are named extravillous trophoblast (EVT) cells, whereas in the rat they are termed invasive trophoblast cells. Mechanisms governing invasive trophoblast cell differentiation remain poorly understood. We investigated peroxisome proliferator-activated receptor gamma (PPARG) as a potential regulator of EVT/invasive trophoblast cell development. In first trimester human placentas, PPARG was expressed in the EVT cell column and increased in amount as human TS cells differentiated into EVT cells. PPARG disruption impaired EVT cell differentiation. Rat invasive trophoblast cells similarly expressed PPARG. Conditional inactivation of PPARG within rat invasive trophoblast cells was used to assess the in vivo role of PPARG on the uterine-placental interface. PPARG was established as an essential cell-autonomous regulator of the invasive trophoblast cells. In conclusion, PPARG is a conserved regulator of placentation and is essential for directing trophoblast cell-guided uterine transformation.

developmental biology↗

bioRxiv2024

NOTUM-MEDIATED WNT SILENCING DRIVES EXTRAVILLOUS TROPHOBLAST CELL LINEAGE DEVELOPMENT

Trophoblast stem (TS) cells have the unique capacity to differentiate into specialized cell types, including extravillous trophoblast (EVT) cells. EVT cells invade into and transform the uterus where they act to remodel the vasculature facilitating the redirection of maternal nutrients to the developing fetus. Disruptions in EVT cell development and function are at the core of pregnancy-related disease. WNT-activated signal transduction is a conserved regulator of morphogenesis of many organ systems, including the placenta. In human TS cells, activation of canonical WNT signaling is critical for maintenance of the TS cell stem state and its downregulation accompanies EVT cell differentiation. We show that aberrant WNT signaling undermines EVT cell differentiation. Notum, palmitoleoyl-protein carboxylesterase (NOTUM), a negative regulator of canonical WNT signaling, was prominently expressed in first trimester EVT cells developing in situ and upregulated in EVT cells derived from human TS cells. Furthermore, NOTUM was required for optimal human TS cell differentiation to EVT cells. Activation of NOTUM in EVT cells is driven, at least in part, by endothelial PAS domain 1 (also called hypoxia-inducible factor 2 alpha). Collectively, our findings indicate that canonical WNT signaling is essential for maintenance of human trophoblast cell stemness and regulation of human TS cell differentiation. Downregulation of canonical WNT signaling via the actions of NOTUM is required for optimal EVT cell differentiation. SIGNIFICANCEExtravillous trophoblast (EVT) cells play a critical role in transforming the uterine environment into a supportive organ facilitating embryonic/fetal development. Insufficient EVT cell-dependent uterine transformation can lead to obstetrical complications, including early pregnancy loss, preeclampsia, intrauterine growth restriction, and preterm birth. These complications carry a significant burden of morbidity and mortality for both the mother and the fetus. Notum, palmitoleoyl-protein carboxylesterase, a WNT signaling antagonist, is involved in promoting and maintaining EVT cell differentiation. This process is essential for the proper development of the placenta and is crucial for a healthy pregnancy.

developmental biology↗