Lin Qimei, Cao Jiasong, Zhu Yu, Yu Jing, Yang Minglei, Liu Zhen, Wang Shuqi, Wang Yixin, Li Xiaohui, Guo Xuemin, Shen Yongmei, Chang Ying
Tianjin Institute of Gynaecology Obsterics, Tianjin Central Hospital of Gynaecology Obstetrics & Nankai University Affiliated Maternity Hospital, Tianjin, 300100, China; Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynaecology Obstetrics, Tianjin, 300100, China.
Tianjin Institute of Gynaecology Obsterics, Tianjin Central Hospital of Gynaecology Obstetrics & Nankai University Affiliated Maternity Hospital, Tianjin, 300100, China; Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin Central Hospital of Gynaecology Obstetrics, Tianjin, 300100, China.
Placenta. 2025 Aug;168:241-252. doi: 10.1016/j.placenta.2025.06.019. Epub 2025 Jul 3.
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 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.
绒毛膜滋养层细胞（CTC）屏障的体内平衡对于维持妊娠至关重要。尽管其激素失衡和免疫功能障碍被认为是早产的促成因素，但物理屏障功能障碍的影响，尤其是在胎膜完整的自发性早产（sPTL）中的影响，仍知之甚少。
比较了足月未临产（TNL）、sPTL和足月临产（TL）组中CTC屏障完整性的生物标志物，包括组织病理学变化、细胞连接蛋白表达和跨膜电阻（TEER）。在原代人CTC（phCTCs）和平滑绒毛膜外植体中研究了活化的17β-雌二醇（E2）/YAP1信号对屏障损伤的影响。使用ELISA测量E2和PAI-1血浆浓度。
sPTL组和TL组均表现出CTC屏障破坏，其特征为TEER降低、细胞连接蛋白表达减少以及KRT6A CTC迁移增加。这些组中YAP1表达和核定位升高，且与CTC迁移增强和细胞旁通透性增加相关。机制上，E2通过ERα直接结合YAP1启动子促进YAP1转录，而抑制YAP1或ERα可显著减轻屏障破坏和CTC迁移。值得注意的是，孕中期母体血浆中PAI-1和E2的浓度有助于预测sPTL（AUC = 0.894）。
活化的E2/ERα-YAP1信号通过损害绒毛膜滋养层细胞完整性导致sPTL。此外，孕中期检测E2与PAI-1的组合为早期识别sPTL高危妊娠提供了可能。
