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 Sol, Miguel A. Esteban, Yasuyuki Ohkawa, Antonio L. Serrano, Eusebio Perdiguero () and Pura Muñoz-Cánoves ()
Additional contact information
Victoria Moiseeva: Pompeu Fabra University
Andrés Cisneros: Pompeu Fabra University
Valentina Sica: Pompeu Fabra University
Oleg Deryagin: Pompeu Fabra University
Yiwei Lai: Chinese Academy of Sciences
Sascha Jung: Bizkaia Technology Park
Eva Andrés: Pompeu Fabra University
Juan An: Chinese Academy of Sciences
Jessica Segalés: Pompeu Fabra University
Laura Ortet: Pompeu Fabra University
Vera Lukesova: Pompeu Fabra University
Giacomo Volpe: Chinese Academy of Sciences
Alberto Benguria: Genomic Unit, Centro Nacional de Investigaciones Cardiovasculares and CIBERCV
Ana Dopazo: Genomic Unit, Centro Nacional de Investigaciones Cardiovasculares and CIBERCV
Salvador Aznar Benitah: ICREA
Yasuteru Urano: The University of Tokyo
Antonio Sol: Bizkaia Technology Park
Miguel A. Esteban: Chinese Academy of Sciences
Yasuyuki Ohkawa: Kyushu University
Antonio L. Serrano: Pompeu Fabra University
Eusebio Perdiguero: Pompeu Fabra University
Pura Muñoz-Cánoves: Pompeu Fabra University

Nature, 2023, vol. 613, issue 7942, 169-178

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-022-05535-x

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