Impaired stem cell migration and divisions in Duchenne Muscular Dystrophy revealed by live imaging

Abstract

Dysregulation of stem cell properties is a hallmark of many pathologies, but the dynamic behaviour of stem cells in their microenvironment during disease progression remains poorly understood. Using the mdx mouse model of Duchenne Muscular Dystrophy, we developed innovative live-imaging of muscle stem cells (MuSCs) in vivo, and ex vivo on isolated myofibres. We show that mdx MuSCs have impaired migration and precocious differentiation through unbalanced symmetric divisions, driven by p38 and PI3K signalling pathways, in contrast to the p38-only dependence of healthy MuSCs. Cross-grafting shows that MuSC fate decisions are governed by intrinsic cues, whereas their migration behaviour is determined by the extracellular niche. This study provides the first dynamic analysis of dystrophic MuSC properties in vivo, reconciling conflicting reports on their function. Our findings establish DMD as a MuSC disease with intrinsic defects and niche dysfunction, offering strategies to restore stem cell functions for improved muscle regeneration.