Macrophage-derived Spp1 promotes an adipogenic stromal cell population that contributes to intramuscular fat in dystrophic muscle

In this study we used macrophage-specific ablation combined with single cell transcriptional profiling to uncover the impact of macrophage derived Spp1 on cell-cell interactions in mdx muscles. Ablation of macrophage-specific Spp1 (cKO) correlated with reduction of two novel PDGFR+ stromal cell populations, expressing Lifr+ and Procr+ in cKO muscles. Sorting and transcriptional profiling of Lifr+ and Procr+ stromal cells confirmed that they are enriched in adipogenesis genes and are highly related to fibroadipogenic precursors (FAPS). These adipogenic stromal cells (ASC) were sorted and cultured and shown to be more adipogenic than FAPS, likely due to a more differentiated state. Reduction of ASCs correlated with reduced intramuscular diaphragmatic fat and improved diaphragm function in cKO compared to mdx controls. These data suggest a role for myeloid-derived Spp1 in the differentiation of stromal cells towards an adipogenic fate, leading to accumulation of intramuscular fat in dystrophic muscles. scRNAseq on mononucleated cells isolated from murine skeletal muscles in Spp1 cKO and WT mice.