Single-cell mapping of maternal-fetal cross-talk in preeclampsia.

Preeclampsia (PE) arises from placental dysfunction, yet the cellular events that distinguish early-onset PE (EOPE) from late-onset PE (LOPE) are poorly defined. We generated a comprehensive single-cell atlas of the placenta of women with and without PE (78 patients), integrating maternal-fetal genotyping, multi-dimensional clustering, and cell-cell communication analysis. PE reshaped the abundance and transcriptional states of major placental cell types. EOPE was defined by expanded T and NK cells with reduced extravillous trophoblasts, whereas LOPE involved increased monocytes/macrophages and activation of ANNEXIN-, NOTCH-, ANGPTL-, and EGF-associated pathways. These onset-specific disruptions reveal distinct modes of immune-trophoblast dysregulation. Extending these insights to maternal circulation, multiple EOPE- and LOPE-derived placental mRNA signatures distinguished EOPE from controls at or after diagnosis, and an EOPE-derived CTB-1 protein signature showed moderate predictive value for LOPE. This atlas defines the cellular architecture of PE subtypes and establishes a foundation for developing early, noninvasive biomarkers.