Abstract
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder involving cycles of muscle degeneration and regeneration, leading to accumulation of intramuscular fibrosis and fat. Ablation of Osteopontin/Spp1 in a murine model of DMD (mdx) improves the dystrophic phenotype, but the source of Spp1 and its impact on target cells in dystrophic muscles remain unknown. In dystrophic muscles, macrophages are the predominate infiltrating leukocyte and express high levels of Spp1. 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 2 PDGFRa+ stromal cell populations, expressing Lifr+ and Procr+. Sorting and transcriptional profiling of these populations confirmed that they are enriched in adipogenesis genes and are highly related to fibroadipogenic precursors (FAPS). These adipogenic stromal cells (ASC) displayed more adipogenic potential in vitro compared with FAPS, likely due to a more differentiated state. Reduction of ASCs correlated with reduced intramuscular diaphragmatic fat and improved diaphragm function. 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.
Authors
Philip K. Farahat, Chino Kumagai-Cresse, Raquel L. Aragón, Feiyang Ma, Justin K. Amakor, Alejandro Espinoza, Irina Kramerova, Robert J. Jimenez, Bradley M. Smith, Jesus Perez, Rachelle H. Crosbie, Apoorva H. Nagendra, Jackie McCourt-Towner, Gerald Coulis, Oluwatayo F. Ikotun, April D. Pyle, Matteo Pellegrini, Elizabeth M. McNally, S. Armando Villalta, Melissa J. Spencer
Figure 1
scRNAseq of muscle-infiltrating mononuclear cells suggests cross talk between myeloid-derived Spp1 and a subpopulation of Pdgfra+ stromal cells.
