Growth differentiation factor 11’s effects on older andyounger donor human mesenchymal stromal cellimmunomodulation, metabolism and senescence

Abstract

Human mesenchymal stromal cells (hMSCs) are strong candidates for cell-based pro-regenerative therapies due to their immunomodulatory and tissue regenerative properties. Due to increases in age-related, inflammatory conditions, this therapeutic approach is becoming more utilised. However, hMSCs are a rare population in the body, requiring significant ex vivo expansion to obtain the numbers required for therapeutic use. This process is particularly challenging for hMSCs derived from older donors (65+), as they typically exhibit reduced therapeutic potential and are more prone to senescence and functional decline. Therefore, new growth conditions to promote expansion which maintain clinically important functional activity are required

Growth differentiation factor 11 (GDF11) has emerged as a promising candidate to counteract age-related decline in cellular function. Serum GDF11 levels have been suggested to decline from ∼60 years old, and its restoration has demonstrated potential rejuvenating effects in murine models. However, the translational relevance of these findings to hMSCs remains unclear.

This study aimed to evaluate whether GDF11 exposure during in vitro expansion could affect the immunomodulatory and pro-regenerative properties of hMSCs from different age groups. hMSCs from younger (19–30 years) and older (65+ years) donors were cultured with various GDF11 regimes. Their immunomodulatory function was assessed via suppression of T cell proliferation, induction of regulatory T cells, and expression of key immunomodulatory proteins PDL-1 and galectin-9 (Gal-9). Effects on mitochondrial dynamics were also evaluated alongside markers of cellular senescence including β galactosidase. Transcriptomic analysis revealed a distinct GDF11-associated gene expression signature and donor-specific variability in response to GDF11 exposure

GDF11 treatment preserved immunomodulatory properties in hMSCs from both age groups. Notably, a subset of older female donor cells demonstrated improved immunomodulation, suggesting some functional rejuvenation. Given the donor variation observed, further studies with larger cohorts are needed to validate GDF11’s potential to enhance hMSC therapies for the ageing population.

Date of Award	Nov 2025
Original language	English
Awarding Institution	Aston University
Supervisor	Ewan Ross (Supervisor), Emma Louise Shepherd (Supervisor) & Cathy Slack (Supervisor)