Wang Bingbing, Seif Karl, Lei Jun, Mangione Mary, Turan Sifa, Reece E Albert, Burd Irina, Yang Peixin
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland.
Am J Perinatol. 2025 Jul;42(10):1333-1343. doi: 10.1055/a-2491-4391. Epub 2024 Nov 29.
Human parturition involves many events among mother, fetus, and placenta, and the initiation of these events is the consequence of activation of a series of endocrine and immune responses. Multiple underlying pathways account for the cascade of events that culminate in spontaneous preterm labor. In this study, we aimed to characterize these signaling pathways of placental origin at molecular levels.We used single-cell RNA-sequencing (sc-RNA-seq) analysis to probe transcriptional heterogeneity in human placenta delivered at preterm or term and then used RNA in situ hybridization (RNA-ISH) assay on formalin-fixed paraffin-embedded (FFPE) placental tissues to validate these results.By using sc-RNA-seq on villous cytotrophoblast (CTB) isolated from a preterm placenta, we found that signaling pathways implicated in the initiation of term or preterm labor including ferroptosis, kisspeptin (), and senescence were constitutively activated in distinct cellular clusters of these trophoblastic stem cells. RNA-ISH-based spatial gene expression profiling in FFPE tissues revealed that pregnancy-specific beta-1-glycoprotein 4 (PSG4), a potent molecular driver for cellular aging, was significantly increased in preterm placentas ( = 30) compared to their full-term counterparts ( = 9). Furthermore, mRNA signals were predominantly detected in the villous syncytiotrophoblast and the discontinuous monolayer of CTB as well as the intervillous space where maternal blood circulates.Our study provides strong support for overexpression serving as a biomarker for pregnant women at risk for preterm delivery, which can allow for the development of timely and clinical preventive strategies. · A sc-RNA-seq analysis on a preterm placenta identified multiple signaling pathways constitutively activated in distinct clusters of CTB.. · RNA-ISH assay uncovered that the mRNA levels of PSG4, a molecular driver for cellular senescence significantly increased in preterm placentas compared to the term counterparts.. · PSG4 mRNA signals were largely observed in the villous trophoblast as well as the intervillous space..
人类分娩涉及母亲、胎儿和胎盘之间的许多事件，这些事件的启动是一系列内分泌和免疫反应激活的结果。多种潜在途径导致了最终引发自发性早产的一系列事件。在本研究中，我们旨在从分子水平上表征这些胎盘来源的信号通路。我们使用单细胞RNA测序（sc-RNA-seq）分析来探究早产或足月分娩的人胎盘的转录异质性，然后对福尔马林固定石蜡包埋（FFPE）的胎盘组织进行RNA原位杂交（RNA-ISH）检测以验证这些结果。通过对从早产胎盘中分离出的绒毛细胞滋养层（CTB）进行sc-RNA-seq分析，我们发现与足月或早产启动相关的信号通路，包括铁死亡、 kisspeptin（）和衰老，在这些滋养层干细胞的不同细胞簇中持续激活。基于RNA-ISH的FFPE组织空间基因表达谱显示，与足月胎盘（n = 9）相比，早产胎盘（n = 30）中细胞衰老的有效分子驱动因子妊娠特异性β-1-糖蛋白4（PSG4）显著增加。此外，mRNA信号主要在绒毛合体滋养层、CTB不连续单层以及母体血液流通的绒毛间隙中检测到。我们的研究为PSG4过表达作为早产高危孕妇的生物标志物提供了有力支持，这有助于制定及时的临床预防策略。· 对早产胎盘的sc-RNA-seq分析确定了在CTB不同簇中持续激活的多种信号通路。· RNA-ISH检测发现，与足月胎盘相比，早产胎盘中细胞衰老分子驱动因子PSG4的mRNA水平显著增加。· PSG4 mRNA信号主要在绒毛滋养层以及绒毛间隙中观察到。
