Integrated multi-omics profiling reveals the potential role of maternal systemic immune dysregulation driven by monocyte/macrophage in preeclampsia.

BACKGROUND

Preeclampsia (PE) is a leading cause of maternal morbidity and mortality, but the coordinated dysregulation between the placental unit and the maternal systemic immune response remains incompletely understood. An integrated multi-omics approach is required to decipher these cross-tissue interactions.

METHODS

We performed an integrated analysis of bulk transcriptome data from 810 pregnancies (299 placental tissues and 511 blood samples). Additionally, to gain mechanistic insights at cellular resolution, we analyzed single-cell RNA sequencing (scRNA-seq) data from maternal endometrial biopsies (from non-pregnant women with a history of PE or Normal, n = 21) and peripheral blood mononuclear cells (PBMCs, n = 10). Analytical methods included differential expression analysis, pathway enrichment, machine learning-based predictive modeling, and cell–cell communication inference.

RESULTS

Analysis of bulk transcriptomes from placental and blood specimens identified 25 core genes consistently associated with PE. A Random Forest model constructed with these genes demonstrated high predictive accuracy (AUC > 0.96 in both tissue and blood) and was validated in an independent cohort (AUC = 0.775). To explore the cellular basis of this signature, we turned to scRNA-seq data. Analysis of maternal endometrium and PBMCs identified a reconfigured immune microenvironment, characterized by an increased proportion of LYZ + monocytes in endometrium from women with a history of PE. A key finding was the significant downregulation of the coagulation factor F13A1 within monocyte/macrophage lineages across both bulk and single-cell datasets. Cell–cell communication analysis further suggested that monocytes/macrophages may regulate immune and endothelial cells through dysregulated COMPLEMENT and GALECTIN signaling pathways.

CONCLUSION

Our study defines a robust, placenta-blood based gene signature for PE. Exploratory analysis of maternal endometrial and immune cells at single-cell resolution provides preliminary evidence that monocyte/macrophage dysfunction, including F13A1 downregulation, may be a pervasive feature of PE pathophysiology, observable even in maternal tissues beyond the placenta. These findings highlight the potential of cross-tissue biomarkers and justify further investigation into the systemic role of myeloid cells in PE.