A cellular and molecular spatial atlas of dystrophic muscle

作者：Michael J. Stec, Qi Su, Christina Adler, Lance Zhang, David R. Golann, Naveen Khan, Lampros Panagis, S. Armando Villalta, Min Ni, Yi Wei, Johnathon R. Walls, Andrew Murphy, George D. Yancopoulos, Gurinder S. Atwal, Sandra Kleiner, Gábor Halász, Mark W. Sleeman · 发表于：Proceedings of the National Academy of Sciences · 年份：2023 · DOI：10.1073/pnas.2221249120 · 被引用次数：29 · 研究领域：Muscle Physiology and Disorders、Single-cell and spatial transcriptomics、Adipose Tissue and Metabolism

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, we 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, we 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.