Matrix stiffness programs mesenchymal stromal cell immunomodulation: A mechano-epigenetic-metabolic perspective for advanced delivery systems

The therapeutic effects of mesenchymal stromal cell (MSC)-based interventions are influenced by the biophysical characteristics of their delivery matrices and the surrounding microenvironment. While matrix stiffness is recognized as an important mechanical cue, the mechanisms linking mechanical forces to sustained immunomodulation remain poorly understood. This review discusses how matrix stiffness may influence MSC immunophenotypes through an integrated mechanotransductive, epigenetic, and metabolic framework. The biophysical signals are transmitted via integrin-mediated adhesions, then can induce lasting epigenetic modifications, including DNA methylation and chromatin remodeling, supported by parallel metabolic reprogramming. Understanding this mechanosensitive regulation can inform the design of biomaterials, including stiffness-matched, dynamically tunable hydrogels and mechanical preconditioning approaches. Such strategies aim to improve MSC survival, modulate secretome profiles, and maintain immunomodulatory functions within stiffened tissue niches. These insights could enhance the development of more effective cell therapies, with implications for controlling MSC behavior in pathologically altered environments.