Asynchronous skeletal muscle degeneration/regeneration is a hallmark feature of Duchenne muscular dystrophy (DMD); however, traditional -omics technologies that lack spatial context make it difficult to study the biological mechanisms of how asynchronous regeneration contributes to disease progression. Here, using the severely dystrophic D2-mdx mouse model, Regeneron Pharmaceuticals researchers generated a high-resolution cellular and molecular spatial atlas of dystrophic muscle by integrating spatial transcriptomics and single-cell RNAseq datasets. Unbiased clustering revealed nonuniform distribution of unique cell populations throughout D2-mdx muscle that were associated with multiple regenerative timepoints, demonstrating that this model faithfully recapitulates the asynchronous regeneration observed in human DMD muscle. By probing spatiotemporal gene expression signatures, the researchers found that propagation of inflammatory and fibrotic signals from locally damaged areas contributes to widespread pathology and that querying expression signatures within discrete microenvironments can identify targetable pathways for DMD therapy. Overall, this spatial atlas of dystrophic muscle provides a valuable resource for studying DMD disease biology and therapeutic target discovery
Single-cell deconvolution of spatial transcriptomics data in dystrophic muscle
(A) Reclustering of skeletal muscle single-cell RNAseq from De Micheli et al. and integration with spatial transcriptomics of dystrophic muscle. (B) Chord diagram displaying co-occurrence of inferred cell types in dystrophic muscle. (C) Heatmap showing the proportion of inferred cell types present within spatial clusters (excluding myofibers). Representative spatial localization and abundance of inferred cell types within Immune 1 (D), Immune 2 (E), and Regn. fiber (F) areas of dystrophic muscle.