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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{
  "DOI": "10.1038/s41556-020-00593-7", 
  "container_title": "Nature Cell Biology", 
  "title": "FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age", 
  "issued": {
    "date-parts": [
      [
        2020, 
        10, 
        26
      ]
    ]
  }, 
  "abstract": "<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>", 
  "author": [
    {
      "family": "Garc\u00eda-Prat,\u00a0Laura"
    }, 
    {
      "family": "Perdiguero,\u00a0Eusebio"
    }, 
    {
      "family": "Alonso-Mart\u00edn,\u00a0Sonia"
    }, 
    {
      "family": "Dell'Orso,\u00a0Stefania"
    }, 
    {
      "family": "Ravichandran,\u00a0Srikanth"
    }, 
    {
      "family": "Brooks,\u00a0Stephen R."
    }, 
    {
      "family": "Juan,\u00a0Aster H."
    }, 
    {
      "family": "Campanario,\u00a0Silvia"
    }, 
    {
      "family": "Jiang,\u00a0Kan"
    }, 
    {
      "family": "Hong,\u00a0Xiaotong"
    }, 
    {
      "family": "Ortet,\u00a0Laura"
    }, 
    {
      "family": "Ruiz-Bonilla,\u00a0Vanessa"
    }, 
    {
      "family": "Fl\u00e1ndez,\u00a0Marta"
    }, 
    {
      "family": "Moiseeva,\u00a0Victoria"
    }, 
    {
      "family": "Rebollo,\u00a0Elena"
    }, 
    {
      "family": "Jard\u00ed,\u00a0Merc\u00e8"
    }, 
    {
      "family": "Sun,\u00a0Hong-Wei"
    }, 
    {
      "family": "Musar\u00f2,\u00a0Antonio"
    }, 
    {
      "family": "Sandri,\u00a0Marco"
    }, 
    {
      "family": "del Sol,\u00a0Antonio"
    }, 
    {
      "family": "Sartorelli,\u00a0Vittorio"
    }, 
    {
      "family": "Mu\u00f1oz-C\u00e1noves,\u00a0Pura"
    }
  ], 
  "page": "1307-1318", 
  "volume": "22", 
  "type": "article", 
  "id": "5844632"
}