Mesenchymal Stromal Cells Are Required for Regeneration and Homeostatic Maintenance of Skeletal Muscle

Summary: The necessity of mesenchymal stromal cells, called fibroadipogenic progenitors (FAPs), in skeletal muscle regeneration and maintenance remains unestablished. We report the generation of a PDGFRαCreER knockin mouse model that provides a specific means of labeling and targeting FAPs. Depletion of FAPs using Cre-dependent diphtheria toxin expression results in loss of expansion of muscle stem cells (MuSCs) and CD45+ hematopoietic cells after injury and impaired skeletal muscle regeneration. Furthermore, FAP-depleted mice under homeostatic conditions exhibit muscle atrophy and loss of MuSCs, revealing that FAPs are required for the maintenance of both skeletal muscle and the MuSC pool. We also report that local tamoxifen metabolite delivery to target CreER activity in a single muscle, removing potentially confounding systemic effects of ablating PDGFRα+ cells distantly, also causes muscle atrophy. These data establish a critical role of FAPs in skeletal muscle regeneration and maintenance. : Wosczyna et al. develop genetic models to target and deplete fibroadipogenic progenitors (FAPs) in skeletal muscle (SkM). Following injury of FAP-depleted SkM, muscle stem cell (MuSC) expansion is impaired, leading to a regenerative deficit. Under homeostatic conditions, FAP-depleted SkM undergoes muscle fiber atrophy, and MuSC numbers decline. Keywords: Mesenchymal, stromal, fibroadipogenic progenitor, FAP, muscle, stem cell, satellite cell, niche, PDGFRα, local recombination