NOTCH, WNT, and TGFβ: Key pathways in extravillous trophoblast formation and differentiation

During gestation, the human placenta ensures nutrition, gas exchange, and protection against pathogens for the growing fetus. As key component in placentation, extravillous trophoblasts (EVTs) arise from trophoblast (TB) progenitors through extensive proliferation at placental tip structures. A stepwise and tightly orchestrated differentiation process enables post-proliferative EVTs to invade maternal uterine layers, remodel the uterine vasculature, and modulate the maternal immune system to sustain pregnancy. Various signaling pathways are crucial in TB biology, including the MAPK, WNT, NOTCH, HIPPO, EGFR, and TGFβ cascades, which have been the subject of numerous comprehensive reviews. Recently developed TB model systems such as TB stem cells and TB organoids have significantly advanced placental research by enabling precise manipulation of signaling pathways and control over TB lineage determination and differentiation. Building on these advancements, this review specifically examines the activity and role of NOTCH, WNT, and TGFβ signaling in the sequential steps of EVT differentiation, integrating key insights gained from TB stem cell- and TB organoid-based studies.