Donor age and sex program MSC secretome signaling: a quadrant framework for precision therapy

Abstract Background Clinical responses to mesenchymal stromal cell (MSC) therapies remain variable because MSCs are often treated as uniform biologics despite donor-programmed differences. Evidence indicates that developmental maturity (fetal vs. adult) and biological sex (female vs. male) bias the MSC secretome and downstream signalling (NF-κB, PI3K/AKT–ERK, TGF-β/Smad, Wnt/β-catenin), potentially shaping anti-inflammatory, angiogenic, anti-fibrotic, and regenerative functions. Methods We conducted a targeted synthesis of peer-reviewed in vitro, preclinical, and early clinical studies that relate donor features (maturity, sex) to secretome mediators (EV miRNAs/proteins; cytokines/growth factors) and pathway readouts. Findings were organized along mediator→pathway→function chains and distilled into a rule-based quadrant model (fetal♀, fetal♂, adult♀, adult♂), with qualitative consideration of tissue source and manufacturing variables. Results Consistent donor-programmed skews emerged: fetal female MSCs enrich IL-10/TSG-6 and miR-125a with NF-κB suppression and Treg/DC-tolerizing activity; fetal male MSCs elevate VEGF/bFGF/HGF with PI3K/AKT–ERK activation supporting angiogenic survival; adult female MSCs show TGF-β/Smad tuning compatible with anti-fibrotic remodelling; adult male MSCs upregulate WNT5A/IGF-1/Runx2, favouring regenerative/osteogenic programmes with comparatively lower oxidative-stress resilience. We translate these patterns into fit-for-purpose potency/CQA panels (e.g., IL-10/TSG-6; VEGF/HGF with pAKT/pERK; TGF-β/Smad; WNT5A/IGF-1/Runx2) and concise trial schemas (stratification by maturity×sex; pathway-anchored pharmacodynamic biomarkers). Conclusions A signaling-centered, donor-stratified framework may help organize heterogeneous findings in the MSC field and generate testable predictions for potency assessment, indication matching, and study design. Because most available evidence evaluates sex or maturity in isolation and under diverse tissue sources and manufacturing conditions, the proposed quadrant model should be interpreted as hypothesis-generating. Prospective, harmonized, head-to-head validation across donor quadrants will be required to determine its translational utility.