Ageing of the skeletal muscle as a barrier to cell therapy: Cell sources, microenvironmental failure and autologous alternatives.

Abstract

The progressive decline of skeletal muscle (SkM) regeneration is a central feature of ageing. In sarcopenia, the age-related loss of muscle mass and function is driven by exhaustion and dysfunction of resident muscle stem cells and by degenerative remodeling of their regenerative niche, including cellular senescence, chronic inflammation, and fibro-adipogenic conversion. Accordingly, cell-based therapies aim to reverse this regenerative failure through direct myofiber replacement, paracrine support of endogenous repair, and immunomodulation of the aged and pathological microenvironment. This comprehensive review examines cell therapy strategies for SkM disorders, including age-related sarcopenia, encompassing satellite cells (SCs), mesenchymal stromal cells (MSCs), pericytes (PCs)/mesoangioblasts, and hematopoietic stem cells (HSCs), and delineates how each population declines with age. A particular focus is placed on breakthroughs in aged-niche conditioning and autologous cell therapy via pluripotent stem cell (PSC) differentiation and direct reprogramming strategies that overcome the donor variability and age-associated functional decline of primary cells. We critically assess preclinical and emerging clinical evidence, highlighting key barriers to translation, and proposing future directions toward restoring regenerative capacity in ageing muscle.