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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{
  "description": "<p><strong>Abstract</strong></p>\n\n<p>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.</p>", 
  "license": "https://creativecommons.org/licenses/by/4.0/legalcode", 
  "creator": [
    {
      "affiliation": "Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada - Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain", 
      "@type": "Person", 
      "name": "Garc\u00eda-Prat,\u00a0Laura"
    }, 
    {
      "affiliation": "Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain", 
      "@type": "Person", 
      "name": "Perdiguero,\u00a0Eusebio"
    }, 
    {
      "affiliation": "Neurosciences Area, Biodonostia Health Research Institute, Donostia-San Sebasti\u00e1n, San Sebasti\u00e1n, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain", 
      "@type": "Person", 
      "name": "Alonso-Mart\u00edn,\u00a0Sonia"
    }, 
    {
      "affiliation": "Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH Bethesda, Bethesda, MD, USA", 
      "@type": "Person", 
      "name": "Dell'Orso,\u00a0Stefania"
    }, 
    {
      "affiliation": "Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg", 
      "@type": "Person", 
      "name": "Ravichandran,\u00a0Srikanth"
    }, 
    {
      "affiliation": "Biodata Mining and Discovery Section, NIAMS, NIH Bethesda, Bethesda, MD, USA", 
      "@type": "Person", 
      "name": "Brooks,\u00a0Stephen R."
    }, 
    {
      "affiliation": "Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH Bethesda, Bethesda, MD, USA", 
      "@type": "Person", 
      "name": "Juan,\u00a0Aster H."
    }, 
    {
      "affiliation": "Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain", 
      "@type": "Person", 
      "name": "Campanario,\u00a0Silvia"
    }, 
    {
      "affiliation": "Biodata Mining and Discovery Section, NIAMS, NIH Bethesda, Bethesda, MD, USA", 
      "@type": "Person", 
      "name": "Jiang,\u00a0Kan"
    }, 
    {
      "affiliation": "Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain", 
      "@type": "Person", 
      "name": "Hong,\u00a0Xiaotong"
    }, 
    {
      "affiliation": "Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain", 
      "@type": "Person", 
      "name": "Ortet,\u00a0Laura"
    }, 
    {
      "affiliation": "Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain", 
      "@type": "Person", 
      "name": "Ruiz-Bonilla,\u00a0Vanessa"
    }, 
    {
      "affiliation": "Grupo de Investigaci\u00f3n en Oncolog\u00eda Cl\u00ednico Traslacional, Instituto de Investigaci\u00f3n Hospital 12 de Octubre, Madrid, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain", 
      "@type": "Person", 
      "name": "Fl\u00e1ndez,\u00a0Marta"
    }, 
    {
      "affiliation": "Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain", 
      "@type": "Person", 
      "name": "Moiseeva,\u00a0Victoria"
    }, 
    {
      "affiliation": "Molecular Imaging Platform, Molecular Biology Institute of Barcelona (IBMB-CSIC), Barcelona, Spain", 
      "@type": "Person", 
      "name": "Rebollo,\u00a0Elena"
    }, 
    {
      "affiliation": "Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain", 
      "@type": "Person", 
      "name": "Jard\u00ed,\u00a0Merc\u00e8"
    }, 
    {
      "affiliation": "Biodata Mining and Discovery Section, NIAMS, NIH Bethesda, Bethesda, MD, USA", 
      "@type": "Person", 
      "name": "Sun,\u00a0Hong-Wei"
    }, 
    {
      "affiliation": "DAHFMO-Unit of Histology and Medical Embryology, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy", 
      "@type": "Person", 
      "name": "Musar\u00f2,\u00a0Antonio"
    }, 
    {
      "affiliation": "Department of Biomedical Science, University of Padova, Padova, Italy", 
      "@type": "Person", 
      "name": "Sandri,\u00a0Marco"
    }, 
    {
      "affiliation": "Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg - CIC bioGUNE, Derio, Spain - IKERBASQUE, Basque Foundation for Science, Bilbao, Spain", 
      "@type": "Person", 
      "name": "del Sol,\u00a0Antonio"
    }, 
    {
      "affiliation": "Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH Bethesda, Bethesda, MD, USA", 
      "@type": "Person", 
      "name": "Sartorelli,\u00a0Vittorio"
    }, 
    {
      "affiliation": "Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain - Spanish National Center on Cardiovascular Research (CNIC), Madrid, Spain - ICREA, Barcelona, Spain", 
      "@type": "Person", 
      "name": "Mu\u00f1oz-C\u00e1noves,\u00a0Pura"
    }
  ], 
  "headline": "FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age", 
  "image": "https://zenodo.org/static/img/logos/zenodo-gradient-round.svg", 
  "datePublished": "2020-10-26", 
  "url": "https://zenodo.org/record/5844632", 
  "@context": "https://schema.org/", 
  "identifier": "https://doi.org/10.1038/s41556-020-00593-7", 
  "@id": "https://doi.org/10.1038/s41556-020-00593-7", 
  "@type": "ScholarlyArticle", 
  "name": "FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age"
}