High-dimensional single-cell cartography reveals novel skeletal muscle resident cell populations

Adult tissue repair and regeneration require the activation of resident stem/progenitor cells that can self-renew and generate differentiated progeny. The regenerative capacity of skeletal muscle relies on muscle satellite cells (MuSCs) and their interplay with different cell types within the niche. Yet, our understanding of the cells that compose the skeletal muscle tissue is limited and molecular definitions of the principal cell types are lacking. Using a combined approach of single-cell RNA-sequencing and mass cytometry, we precisely mapped the different cell types in adult skeletal muscle tissue and highlighted previously overlooked populations. We identified known functional populations, characterized their gene signatures, and determined key markers. Among the ten main cell populations present in skeletal muscle, we found an unexpected complexity in the interstitial compartment and identified two new cell populations. One express the transcription factor Scleraxis and generate tenocyte-like cells. The second express smooth muscle and mesenchymal cell markers (SMMCs). While distinct from MuSCs, SMMCs are endowed with myogenic potential and promote MuSC engraftment following transplantation. Our high-dimensional single-cell atlas uncovers principles of an adult tissue composition and can be exploited to reveal unknown cellular sub-fractions that contribute to tissue regeneration.