Researchers of the Stanford University College of Medicine have just published an important paper on FAP mesenchymal stromal cells in muscle regeneration.
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.
We demonstrate that FAP cells are required in the early stages of skeletal muscle regeneration, supporting MuSC and HC expansion in the area of injury. We also demonstrate that FAPs are required for long-term homeostatic maintenance of adult skeletal muscle as well as homeostatic maintenance of the MuSC pool. Our findings establish FAPs as beneficial components of these processes, and they are of particular interest, given that FAPs are also thought to be a key source of detrimental fatty and fibrotic infiltration in skeletal muscle observed in muscular dystrophies and the normal aging process. It will be especially interesting to determine the beneficial influence of FAPs on MuSCs and HCs in the regenerative milieu and on MuSCs and myofibers in long-term maintenance and growth of skeletal muscle; therapeutically targeting these mechanisms may provide a means to aid skeletal muscle regeneration or help maintain skeletal muscle over the normal course of aging.