TFEB safeguards trophoblast syncytialization in humans and mice (human RNA-Seq)

Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent research demonstrates that the placenta adapts to nutrient insufficiency through mTOR inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype directing extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. Endogenous TFEB deficiency significantly impaired STB differentiation in trophoblast cells and placenta organoids. Mechanistically, TFEB conferred direct transcriptional regulation of the fusogen ERVFRD-1 in human trophoblasts and thereby profoundly promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. In line with the in vitro findings, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Moreover, TFEB directs the trophoblast syncytialization response driven by mTORC1 signaling. Importantly, TFEB expression positively correlates with the reinforced trophoblast syncytialization in human fetal growth restriction (FGR) placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.