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

Victoria Moiseeva, Andrés Cisneros, Valentina Sica, Oleg Deryagin, Yiwei Lai, Sascha Jung, Eva Andrés, Juan An, Jessica Segalés, Laura Ortet, Vera Lukesova, Giacomo Volpe, Alberto Benguria, Ana Dopazo, Salvador Aznar-Benitah, Yasuteru Urano, Antonio del Sol, Miguel A. Esteban, Yasuyuki Ohkawa, Antonio L. SerranoEusebio Perdiguero, Pura Muñoz-Cánoves

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. 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 scarcity3 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 (inflammageing4) 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.

Original languageEnglish
Pages (from-to)169-178
Number of pages10
JournalNature
Volume613
Issue number7942
DOIs
Publication statusPublished - Jan 5 2023

All Science Journal Classification (ASJC) codes

  • General

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