Aberrant fibro-adipogenic progenitor subpopulations drive volumetric muscle loss-induced fibrosis

Volumetric muscle loss (VML) injuries result in chronic fibrosis, inflammation, and persistent functional deficits. Fibro-adipogenic progenitor (FAP) cells are a heterogeneous, muscle-resident stromal cell population that play a crucial role in muscle regeneration but also contribute to fibrosis in muscle disease. The role of FAPs in VML is not well established and may be a critical target to ensure functional muscle regeneration after VML. We utilized a critical VML model in the mouse quadriceps, compared with subcritical injuries and uninjured controls, to study the single-cell transcriptional profile of FAPs after VML. Our findings establish an aberrant FAP subpopulation that is elevated in VML injury and provide novel targets for future scarless muscle regeneration in VML. Subcritical injuries and critical VML defects were created in the mouse left quadriceps, and animals were euthanized 7 days post-injury. Uninjured quadriceps were used as naïve controls. Single cells from quadriceps were isolated, processed, and stained for CITE-seq study. Four animals were included in each group.