FoxO3a Directs a Protective Autophagy Program in Hematopoietic 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: 41.46). 02/2013; 494(7437). DOI: 10.1038/nature11895
Source: PubMed


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.

15 Reads
    • "Lower mTOR signaling can induce autophagy, which in turn could contribute to the decreased ribosome content of D/D cells. We analyzed the expression of genes encoding the core autophagy machinery and several genes whose expression defines a pro-autophagic signature (Warr et al., 2013) by qPCR. Expression of the pro-autophagy signature genes was either unaltered (Bnip3) or slightly lower (Sesn1, Bbc3) in D/D Flt3 À LS cells (Figure 5A). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcription factor RUNX1 is frequently mutated in myelodysplastic syndrome and leukemia. RUNX1 mutations can be early events, creating preleukemic stem cells that expand in the bone marrow. Here we show, counterintuitively, that Runx1-deficient hematopoietic stem and progenitor cells (HSPCs) have a slow growth, low biosynthetic, small cell phenotype and markedly reduced ribosome biogenesis (Ribi). The reduced Ribi involved decreased levels of rRNA and many mRNAs encoding ribosome proteins. Runx1 appears to directly regulate Ribi; Runx1 is enriched on the promoters of genes encoding ribosome proteins and binds the rDNA repeats. Runx1-deficient HSPCs have lower p53 levels, reduced apoptosis, an attenuated unfolded protein response, and accordingly are resistant to genotoxic and ER stress. The low biosynthetic activity and corresponding stress resistance provides a selective advantage to Runx1-deficient HSPCs, allowing them to expand in the bone marrow and outcompete normal HSPCs. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell stem cell 07/2015; 17(2). DOI:10.1016/j.stem.2015.06.002 · 22.27 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study is to understand the role of hepatocyte senescence in development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. Insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 were evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells. In addition, changes in GLUT expression can be used as surrogate markers of hepatocyte senescence.
    Experimental Cell Research 09/2014; DOI:10.1016/j.yexcr.2014.09.025 · 3.25 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tissue homeostasis and regenerative capacity rely on rare populations of somatic stem cells endowed with the potential to self-renew and differentiate. During aging, many tissues show a decline in regenerative potential coupled with a loss of stem cell function. Cells including somatic stem cells have evolved a series of checks and balances to sense and repair cellular damage to maximize tissue function. However, during aging the mechanisms that protect normal cell function begin to fail. In this review, we will discuss how common cellular mechanisms that maintain tissue fidelity and organismal lifespan impact somatic stem cell function. We will highlight context-dependent changes and commonalities that define aging, by focusing on three age-sensitive stem cell compartments: blood, neural, and muscle. Understanding the interaction between extrinsic regulators and intrinsic effectors that operate within different stem cell compartments is likely to have important implications for identifying strategies to improve health span and treat age-related degenerative diseases.
    Current Topics in Developmental Biology 01/2014; 107C:405-438. DOI:10.1016/B978-0-12-416022-4.00014-7 · 4.68 Impact Factor
Show more

Preview (2 Sources)

15 Reads
Available from