Estrogen-induced YAP1 activation disrupts chorionic trophoblast barrier integrity in spontaneous preterm labor

The homeostasis of chorionic trophoblast cell (CTC) barrier is essential for maintaining pregnancy. Although its hormone imbalanced and immune dysfunction are recognized as contributors of premature birth, the impact of physical barrier dysfunction, particularly in spontaneous premature labor with intact fetal membranes (sPTL), remains poorly understood.

Biomarkers of CTC barrier integrity, including histopathological changes, cell junction protein expression, and transmembrane electrical resistivity (TEER), were compared in term not in labor (TNL), sPTL, and term in labor (TL) groups. The impact of activated 17β-estradiol (E2)/YAP1 signaling on barrier damage was investigated in primary human CTCs (phCTCs) and smooth chorionic explants. E2 and PAI-1 plasma concentrations were measured using ELISA.

Both sPTL and TL groups exhibited CTC barrier disruption, characterized by decreased TEER and cell junction protein expression, and increased migration of KRT6A^high CTCs. YAP1 expression and nuclear localization were elevated in these groups and correlated with enhanced CTCs migration and increased paracellular permeability. Mechanistically, E2 promoted YAP1 transcription through direct binding of ERα to the YAP1 promoter, while YAP1 or ERα inhibition significantly attenuated barrier disruption and CTC migration. Notably, maternal plasma concentrations of PAI-1 and E2 in the second trimester contribute to sPTL prediction (AUC = 0.894).

Activated E2/ERα-YAP1 signaling contributes to sPTL by compromising chorionic trophoblast cell integrity. Moreover, the combination of E2 with PAI-1 detection during the second trimester offers the potential for early identification of high-risk pregnancies for sPTL.