Objective: Human parturition involve 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.
Study design: 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 placental tissues to validate these results.
Results: By using sc-RNA-seq on villous cytotrophoblast isolated from a preterm placenta, we found that signaling pathways implicated in 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 formalin-fixed paraffin-embedded tissues revealed that Pregnancy Specific beta-1-Glycoprotein 4 (PSG4), a potent molecular driver for cellular aging, was significantly increased in preterm placentas (N=30) compared to their full-term counterparts (N=9). Furthermore, PSG4 mRNA signals were predominantly detected in the villous syncytiotrophoblast and the discontinuous monolayer of cytotrophoblast as well as the intervillous space where maternal blood circulates.
Conclusions: Our study provides strong support for PSG4 overexpression serving as a biomarker for pregnant women at risk for preterm delivery, which can allow for development of timely and clinical preventive strategies.
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