Single-cell transcriptome analyses reveal disturbed decidual microenvironment in women of advanced maternal age

Abstract

Background: Advanced maternal age (AMA) increases pregnancy risk. However, uterine-specific mechanisms independent of oocyte and embryo quality remain poorly defined. This study aimed to characterise the decidual microenvironment in women with AMA to identify key pathological changes and regulatory pathways.

Methods and results: Through integrated histology, organoid modelling, and high-resolution scRNA-seq of first-trimester decidua from women of AMA and controlled reproductive age, we uncovered a pathologically remodelled decidual microenvironment characterised by aberrant cellular states and pathological differentiation pathways, leading to a pro-fibrotic state and accompanied by immune cell dysfunction, and disrupted intercellular communication in the AMA decidua. Central to this pathology was hyperactivated TGF-β signalling, driving fibroblast-to-myofibroblast transition and extracellular matrix overproduction, thereby fuelling fibrosis. Aberrant TGF-β further impaired decidual stromal cell (DSC) differentiation, leading to the failure of the essential mesenchymal-to-epithelial transition. We identified PRR15 as a novel DSC-specific regulator that is markedly suppressed in AMA. PRR15 deficiency unleashed hyperactive TGF-β/SMAD signalling, directly causing decidualisation failure, enhanced fibrosis, and aborted DSC differentiation. Epithelial–mesenchymal transition and immune cell reprogramming towards pro-fibrotic transcriptional signatures further amplify the fibrotic pathology.

Conclusion: This study established the aged decidual microenvironment, orchestrated by dysregulated TGF-β signalling and PRR15 loss, as a critical independent determinant of reproductive failure in AMA. Thus, it unveils novel diagnostic and therapeutic targets and strategies.

Keywords

advanced maternal age, decidualisation / decidua fibrosis, epithelial–mesenchymal transition, fibroblast–myofibroblast transition, PRR15-TGF-β axis, single cell RNA sequencing

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