Donor age and sex shape MSC secretome signalling · a framework for potency testing
This targeted synthesis proposes a quadrant framework (fetal/adult x female/male) for understanding how donor characteristics programme mesenchymal stromal cell secretomes. Each quadrant showed distinct signalling biases: fetal female MSCs favoured anti-inflammatory pathways, fetal male angiogenic, adult female anti-fibrotic, and adult male regenerative/osteogenic. The authors translate these patterns into fit-for-purpose potency and critical quality attribute panels for cell therapy manufacturing.
The original study
Donor age and sex program MSC secretome signaling: a quadrant framework for precision therapy.
- Authors
- Azad T, Hong K, Wu F, Mao J, Zhou X, Xie H, et al.
- Journal
- Stem cell research & therapy
- PMID
- 41877175
Original 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.