A Synergistic Biomaterial/Pharmacologic Approach to Rejuvenate the Aged Muscle Stem Cell Population

Impaired muscle strength and regeneration are major problems of aging. We found that skeletal muscle stem cells (MuSCs) from aged mice are two-thirds less effective in regenerating muscle than young MuSCs, even in a young microenvironment. Culture of aged MuSCs in hydrogel niches in conjunction with a pharmacological inhibitor of p38 mitogen-activated protein kinase, induced MuSC self-renewal in culture and decreased the proportion expressing p21 and p16^Ink4a. The capacity of this population to regenerate damaged muscles was similar to young MuSCs following transplantation into mice, evaluated by non-invasive imaging, stem-cell repopulation, and serial transplantation assays. The rejuvenation of the aged muscle stem cell population was attributable to expansion of a functional subpopulation, as revealed by time-lapse microscopy. Molecular analyses identified a mechanism whereby substrate mechanics contributes to the modulation of MuSC stemness.  Notably, strength was restored when the rejuvenated population was delivered to damaged muscles of aged mice. These findings suggest that a localized autologous muscle stem cell therapy post-injury could benefit aged individuals.