High-Dimensional Single-Cell Cartography Reveals Novel Skeletal Muscle Resident Cell Populations

Abstract

Adult tissue repair and regeneration require the activation of resident stem and 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. However, our understanding of the cells that compose skeletal muscle tissue is limited and molecular definitions of the principal cell types are lacking. Here, using a novel combined approach of single-cell RNA-sequencing and mass cytometry, we precisely mapped 10 different cell types in adult mouse skeletal muscle, including two previously unidentified populations. We also characterized the gene signatures and determined the key discriminating markers of each cell type. We found an unexpected complexity in the interstitial compartment, wherein two new cell populations were identified. One population expressed the transcription factor Scleraxis and generated tenocytes in vitro. The second population expressed smooth muscle and mesenchymal cell (SMMC) markers and, while distinct from MuSCs, exhibited myogenic potential and promoted MuSC engraftment following transplantation. The blueprint presented here yields crucial insights into muscle-resident cell type identities and can be exploited to study muscle ageing and diseases.