Senescent Cells Inhibit Muscle Stem Cell Function and Regenerative Capacity

Researchers here report on evidence for senescent cells in the stem cell niches supporting muscle tissue to reduce stem cell function and the capacity for muscle regeneration. Senescent cells accumulate with age throughout the body, and their inflammatory secretions are disruptive to tissue function. The development of many varied approaches to selectively destroy these errant cells is well underway in the biotech community, with the hope that late life health will be greatly improved as a result.

Tissue regeneration requires coordination between resident stem cells and local niche cells. 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 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) 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.

Link: https://doi.org/10.1038/s41586-022-05535-x

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