Tissue damage leads to a conserved stress response that initiates quiescent muscle stem cell activation

In multicellular organisms, cells dynamically interact with the microenvironment, which determines their properties and gene-expression profile. Tissue damage, such as injury or experimental cell dissociation, leads to dramatic modifications of the niche, yet the early cellular responses in vivo remain ill-defined. We have generated single cell and nucleus atlases from intact, dissociated and injured muscle and liver, and identified a common stress response signature. This prevalent stress response was also detected in published datasets across tissues, demonstrating high conservation but also indicating a significant degree of data distortion in single-cell reference atlases. Using quiescent muscle stem cells as a paradigm of cell activation during tissue repair, we captured the kinetics of the early response to muscle injury. We show that an essential ERK1/2 primary proliferation signal precedes the initiation of the Notch-regulated myogenic program. Our study, therefore, defines the initial events priming cell activation following perturbations in tissue integrity in vivo and identifies a broadly conserved transcriptional stress response that acts in parallel to cell-specific adaptive alterations Overall design: Study of tissue dissociation and injury in mouse skeletal muscle stem cells, liver and muscle single-nuclei