Single-cell chromatin accessibility profiling reveals a self-renewing muscle satellite cell state

A balance between self-renewal and differentiation is critical for the
regenerative capacity of tissue-resident stem cells. In skeletal muscle,
successful regeneration requires the orchestrated activation,
proliferation, and differentiation of muscle satellite cells (MuSCs) that
are normally quiescent. A subset of MuSCs undergoes self-renewal to
replenish the stem cell pool, but the features that identify and define
self-renewing MuSCs remain to be elucidated. Here, through single-cell
chromatin accessibility analysis, we reveal the self-renewal versus
differentiation trajectories of MuSCs over the course of
regeneration in vivo. We identify Betaglycan as a unique marker of
self-renewing MuSCs that can be purified and efficiently contributes to
regeneration after transplantation. We also show that SMAD4 and downstream
genes are genetically required for self-renewal in vivo by restricting
differentiation. Our study unveils the identity and mechanisms of
self-renewing MuSCs while providing a key resource for comprehensive
analysis of muscle regeneration.