Mapping Decidualization Resistance in Former Severe Preeclampsia Patients at Multi-Omic Levels

Abstract Endometrial decidualization resistance (DR) is implicated in various gynaecological and obstetric conditions. Employing a multi-omic strategy, we unraveled the cellular and molecular characteristics of DR in patients that have suffered severe preeclampsia (sPE). Morphological analysis unveiled significant glandular anatomical abnormalities, confirmed histologically. Single-cell RNA sequencing (scRNA-seq) of endometrial samples from sPE cases (n=11) and controls (n=12) revealed sPE-associated shifts in cell composition, manifesting as a stromal mosaic state characterized by proliferative stromal cells (MMP11, SFRP1+) alongside IGFBP1+ decidualized cells, with concurrent epithelial mosaicism and a dearth of epithelial-stromal transition associated with decidualization. Cell-cell communication network mapping underscored aberrant crosstalk among specific cell types, implicating crucial pathways such as endoglin and WNT. Spatial transcriptomics in a replication cohort validated DR-associated features. Laser capture microdissection/mass spectrometry in a second replication cohort corroborated several scRNA-seq findings, notably the absence of stromal to epithelial transition at a pathway level, indicating disrupted response to steroid hormones, particularly estrogens. These insights shed light on potential molecular mechanisms underpinning DR pathogenesis in the context of sPE.