CD146 + interstitial cells contribute to the dystrophic skeletal muscle phenotype in vitro

CD146 + interstitial cells are myogenic progenitors which contribute to skeletal muscle regeneration. However, their role in Duchenne muscular dystrophy (DMD) remains unclear. We compared CD146 + cells from wild-type and mdx mice, revealing distinct molecular and functional differences. Mdx CD146 + differentiated less efficiently into myoblasts and multinucleated myotubes but more efficiently into fibroblasts and adipocytes in vitro. Conditioned medium from mdx CD146 + cells impaired endothelial cell differentiation, through dysregulation of Sdf-1 and Angpt2 secretion. Transcriptomic analyses further reveal a dysregulation of key muscle-related and pro-angiogenic genes, along with an upregulation of fibrosis-associated factors. Mechanistically, we identify changes in the NF-κB, c-Jun, and c-Fos pathways activity as contributors to these pathological changes. These findings suggest that CD146 + cells may play a previously unrecognized role in promoting muscle fibrosis and vascular dysfunction in DMD, rather than aiding regeneration as observed in wild-type.