Multimodal single cell profiling of Duchenne Muscular Dystrophy
Overview
Invité par Rémi MOUNIER
Abstract
Duchenne muscular dystrophy (DMD) is one of the most severe pediatric degenerative myopathies. In the initial phase of the disease, muscle is exposed to continuous cycles of degeneration and regeneration; over time, regenerative potential is exhausted, and necrosis prevails. As of today, the cellular and molecular determinants responsible for this functional exhaustion remain largely uncharacterized.
Adult tissue repair requires the activation of resident stem cells that can both self-renew and generate differentiated progeny. To establish and maintain their properties, stem cells require constant interactions with their microenvironment and their neighboring cells that altogether constitute the niche. The stem cell and its niche form as a whole the minimum functional unit of adult tissue repair. Any given perturbation affecting either the stem cell or the molecular/cellular components of the niche will invariantly impact repair potential. Therefore, in DMD the changes hindering the correct execution of the repair process must therefore occur either in the stem cell or in its niche.
Here we present a multi-omic Spatial strategy to elucidate the determinants interfering with regeneration in the dystrophic muscle and study the niche-stem cell interactions. By leveraging multi-modal data integration (Spatial transcriptomics, snRNAseq and snATACseq), we assessed changes in cell-type compositions, their spatial relationships and dependencies on other cell types, and the evolution of their respective crosstalk. Through our approach, we highlight the changes that occur in the transcriptome and muscle epigenome during disease progression in those regions associated with injury, regeneration, and degeneration. In conclusion, our study delivers an integrative molecular map of dystrophic muscle and lays the groundwork for future studies aimed at the identification of novel biomarkers and potential therapeutic approaches to promote muscle regeneration.
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