October 26, 2020 Preprint Open Access

García-Prat, Laura; Perdiguero, Eusebio; Alonso-Martín, Sonia; Dell'Orso, Stefania; Ravichandran, Srikanth; Brooks, Stephen R.; Juan, Aster H.; Campanario, Silvia; Jiang, Kan; Hong, Xiaotong; Ortet, Laura; Ruiz-Bonilla, Vanessa; Flández, Marta; Moiseeva, Victoria; Rebollo, Elena; Jardí, Mercè; Sun, Hong-Wei; Musarò, Antonio; Sandri, Marco; del Sol, Antonio; Sartorelli, Vittorio; Muñoz-Cánoves, Pura

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  <dc:creator>García-Prat, Laura</dc:creator>
  <dc:creator>Perdiguero, Eusebio</dc:creator>
  <dc:creator>Alonso-Martín, Sonia</dc:creator>
  <dc:creator>Dell'Orso, Stefania</dc:creator>
  <dc:creator>Ravichandran, Srikanth</dc:creator>
  <dc:creator>Brooks, Stephen R.</dc:creator>
  <dc:creator>Juan, Aster H.</dc:creator>
  <dc:creator>Campanario, Silvia</dc:creator>
  <dc:creator>Jiang, Kan</dc:creator>
  <dc:creator>Hong, Xiaotong</dc:creator>
  <dc:creator>Ortet, Laura</dc:creator>
  <dc:creator>Ruiz-Bonilla, Vanessa</dc:creator>
  <dc:creator>Flández, Marta</dc:creator>
  <dc:creator>Moiseeva, Victoria</dc:creator>
  <dc:creator>Rebollo, Elena</dc:creator>
  <dc:creator>Jardí, Mercè</dc:creator>
  <dc:creator>Sun, Hong-Wei</dc:creator>
  <dc:creator>Musarò, Antonio</dc:creator>
  <dc:creator>Sandri, Marco</dc:creator>
  <dc:creator>del Sol, Antonio</dc:creator>
  <dc:creator>Sartorelli, Vittorio</dc:creator>
  <dc:creator>Muñoz-Cánoves, Pura</dc:creator>
  <dc:date>2020-10-26</dc:date>
  <dc:description>Abstract

Tissue regeneration declines with ageing but little is known about whether this arises from changes in stem-cell heterogeneity. Here, in homeostatic skeletal muscle, we identify two quiescent stem-cell states distinguished by relative CD34 expression: CD34High, with stemness properties (genuine state), and CD34Low, committed to myogenic differentiation (primed state). The genuine-quiescent state is unexpectedly preserved into later life, succumbing only in extreme old age due to the acquisition of primed-state traits. Niche-derived IGF1-dependent Akt activation debilitates the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive a primed-to-genuine state conversion, whereas FoxO inactivation deteriorates the genuine state at a young age, causing regenerative failure of muscle, as occurs in geriatric mice. These findings reveal transcriptional determinants of stem-cell heterogeneity that resist ageing more than previously anticipated and are only lost in extreme old age, with implications for the repair of geriatric muscle.</dc:description>
  <dc:identifier>https://zenodo.org/record/5844632</dc:identifier>
  <dc:identifier>10.1038/s41556-020-00593-7</dc:identifier>
  <dc:identifier>oai:zenodo.org:5844632</dc:identifier>
  <dc:relation>info:eu-repo/grantAgreement/EC/H2020/645648/</dc:relation>
  <dc:relation>info:eu-repo/grantAgreement/EC/H2020/825825/</dc:relation>
  <dc:relation>info:eu-repo/grantAgreement/EC/H2020/741966/</dc:relation>
  <dc:relation>url:https://zenodo.org/communities/upgrade-h2020-project</dc:relation>
  <dc:rights>info:eu-repo/semantics/openAccess</dc:rights>
  <dc:rights>https://creativecommons.org/licenses/by/4.0/legalcode</dc:rights>
  <dc:source>Nature Cell Biology 22 1307-1318</dc:source>
  <dc:title>FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age</dc:title>
  <dc:type>info:eu-repo/semantics/preprint</dc:type>
  <dc:type>publication-preprint</dc:type>
</oai_dc:dc>