Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration

Tissue regeneration requires coordination between resident stem cells and local niche cells(1,2). Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity(3) was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing(4)) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.

Automated summary

This study reveals that senescent cells are crucial components of the skeletal muscle regenerative niche and inhibit regeneration. Through single-cell transcriptomics and senescent-cell enrichment sorting, different types of senescent cells were identified and isolated from damaged muscles of young and old mice. The findings demonstrate that senescent cells create an aged-like inflamed niche and impair stem cell proliferation and regeneration.