CD90 identifies distinct fractions of muscle stem cells with different modalities of activation and quiescence maintenance

Stem cell transition from quiescence to activation is crucial to guarantee productive tissue regeneration. Here we show that CD90 diversifies quiescent muscle stem cells (MuSCs) in murine and human muscle into two subpopulations differing in the kinetics of activation, CD90 ^+ve MuSCs exhibiting a faster exit quiescence and predominating the initial phases of regeneration compared to CD90 ^-ve MuSCs. In the absence of injury, the CD90 ^+ve fraction is primed toward activation through an active CD90-AMPK axis but is maintained in quiescence through signals from the extracellular matrix. Our studies show that Collagen VI, which is preferentially expressed by CD90 ^+ve MuSCs, binds to the Calcitonin receptor and plays a role in this context. Moreover, while the number of CD90 ^+ve and CD90 ^-ve subpopulations is similar in healthy muscles, the CD90 ^-ve fraction predominates in the muscles of murine models of Duchenne and Ullrich congenital muscular dystrophies. These findings provide novel insights into the mechanistic determinants of MuSCs functional heterogeneity and have implications for understanding the stimulation of repair in dystrophic muscle.