What question did this study set out to answer?

Investigate how donor age and sex influence the secretome of mesenchymal stromal cells (MSCs) and their signaling pathways.

March 26, 2026Open Access

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

Key Points

Investigate how donor age and sex influence the secretome of mesenchymal stromal cells (MSCs) and their signaling pathways.
Synthesized peer-reviewed in vitro, preclinical, and early clinical studies on MSCs.
Analyzed the impact of donor maturity (fetal vs. adult) and sex (female vs. male) on the MSC secretome.
Developed a quadrant model categorizing MSCs based on donor characteristics and pathway outcomes.
Identified distinct secretome patterns linked to donor characteristics leading to different signaling pathways.
Fetal female MSCs showed enhanced anti-inflammatory responses, while fetal male MSCs promoted angiogenic survival.
Adult male and female MSCs were associated with different regenerative and anti-fibrotic functions, respectively.

Abstract

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. 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. 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). 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.

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