Myoblast transplantation has been investigated as a treatment for Duchenne Muscular Dystrophy and injured myocardial tissue. Multiple groups have isolated an early myogenic precursor population, termed muscle-derived stem cells (MDSCs) that have a superior ability to regenerate dystrophin-positive myofibers and improve cardiac function following an ischemic event as compared to more differentiated myoblasts. The initial local environment of these transplantations involves a high degree of inflammation and its associated major component, oxidative stress. Here, we report that a resistance to these stresses is an important factor determining the regenerative capacity of muscle stem cells in skeletal and cardiac muscle. MDSCs have an increased antioxidant capacity that protects them from intracellular oxidative damage while myoblasts have lower levels of survival and delayed differentiation following exposure to oxidative stress. These experiments were conducted using a series of high throughput assays that combine robotic live-cell microscopy with custom image analysis software. Further, when antioxidant levels in MDSCs are lowered to values comparable to myoblasts, the regenerative capacity of MDSCs decreases to levels comparable to myoblasts in both skeletal muscle and cardiac cell therapies. These findings indicate the important role inflammation plays in cell therapies, and identifies an important new mechanism by which stem cells display a unique regenerative capacity and also a new phenotype in selecting cell populations with enhanced regeneration capacity
