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FOXO3A directs a protective autophagy program in haematopoietic stem cells

The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Division of Hematology/Oncology, University of California San Francisco, San Francisco, California 94143, USA.
Nature (Impact Factor: 42.35). 02/2013; 494(7437). DOI: 10.1038/nature11895
Source: PubMed

ABSTRACT Blood production is ensured by rare, self-renewing haematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy after ex vivo cytokine withdrawal and in vivo calorie restriction. We demonstrate that FOXO3A is critical to maintain a gene expression program that poises HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FOXO3A-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.

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    • "A study in yeast demonstrated increased gluconeogenesis and glycogenesis as hallmarks of ageing [39]. A more recent study indicated defects in glucose uptake in older haematopoietic stem cells [40]. These studies not only corroborate the notion that cellular senescence is associated with insulin resistance, but also indicate that this phenomenon is not limited to a particular cell type. "
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    • "Is aging of the stem cell caused by a decline in autophagy? Recently, Passegue and colleagues challenged this notion (Warr et al., 2013). The authors revealed that freshly isolated aged HSCs have basal levels of autophagy, unlike adult HSCs that only when activated and stressed, mount an autophagic response. "
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    Current Topics in Developmental Biology 01/2014; 107C:405-438. DOI:10.1016/B978-0-12-416022-4.00014-7 · 4.21 Impact Factor
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    • "9 undamaged FOXO3A-driven pro-autophagy gene program, and enduring autophagy is necessary to alleviate an energy crisis and permit their continued existence (Warr et al., 2013; Bowman and Zon 2013) The function of autophagy is to serve as an important source of amino acids for gluconeogenesis and other systemic oxidative and biosynthetic reactions when exogenous substrate is not available. "
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