Individual-dependent molecular heterogeneity in human endometrial stromal cells: a potential determinant of female fertility.

BACKGROUND: Human endometrial stromal cells (hEnSCs) are central to female fertility. This study investigated the cellular and molecular landscape of hEnSCs and identified inter-individual variations that may influence reproductive potential. METHODS AND RESULTS: Endometrial biopsies were obtained from 16 women undergoing gynecologic evaluation. Primary hEnSCs were isolated, expanded, and characterized for mesenchymal stem cell properties. Stemness, receptivity, and decidualization capacity were assessed using RT-qPCR and RNA sequencing, followed by differential gene expression and pathway enrichment analyses. Integrated cellular and transcriptomic analyses revealed donor-dependent molecular heterogeneity. Key genes involved in stemness (OCT4, KLF4, MYC), decidualization (PRL, IGFBP1), and endometrial receptivity (ESR1, PGR, HOXA10, and HOXA11) showed significant variability among individuals. RNA-seq analyses further identified differentially expressed genes associated with clinical variables, including age, body mass index (BMI), and endometrial thickness. Age-related transcriptomic changes included enrichment of genes involved in extracellular matrix organization, cell adhesion, and immune regulation. A higher BMI was connected to altered regulation of genes related to the cell cycle, extracellular matrix, and signaling receptor regulatory activity, while a thin endometrium was associated with downregulation of genes involved in cell-cell junction, signaling receptor regulatory activity, and epidermal development. CONCLUSION: hEnSCs exhibit significant individual-dependent molecular heterogeneity, with donor-specific variations influencing crucial biological pathways related to receptivity, stemness, and decidualization. These molecular profiles, influenced by age, BMI, and endometrial thickness, may reflect the fertility potential of the endometrium. Recognition of such intrinsic, individual-specific endometrial variation emphasizes the importance of personalized approaches in fertility assessment and reproductive treatments.