Hematopoietic stem cell aging: Mechanism and consequence

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Experimental Gerontology (Impact Factor: 3.53). 06/2007; 42(5):385-90. DOI: 10.1016/j.exger.2006.11.019
Source: PubMed

ABSTRACT Advancing age is frequented by the onset of a variety of hematological conditions characterized by diminished homeostatic control of blood cell production. The fact that upstream hematopoietic stem and progenitor cells are obligate mediators of homeostatic control of all blood lineages, has implicated the involvement of these cells in the pathophysiology of these conditions. Indeed, evidence from our group and others has suggested that two of the most clinically significant age-associated hematological conditions, namely, the diminution of the adaptive immune system and the elevated incidence of myeloproliferative diseases, have their origin in cell autonomous changes in the functional capacity of hematopoietic stem cells.

  • Source
    • "Stem cells maintain tissue homeostasis by replacing damaged or worn-out cells and the deterioration of stem-cell functions, including self-renewal capacity, is one of the key components of organismal ageing (Janzen et al, 2006; Molofsky et al, 2006; Rossi et al, 2007, 2008). Distinct metabolic programmes in stem cells are necessary to protect genomic stability and to generate precursors for macromolecular synthesis to facilitate continued self-renewal. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Forkhead Box O (FoxO) transcription factors act in adult stem cells to preserve their regenerative potential. Previously, we reported that FoxO maintains the long-term proliferative capacity of neural stem/progenitor cells (NPCs), and that this occurs, in part, through the maintenance of redox homeostasis. Herein, we demonstrate that among the FoxO3-regulated genes in NPCs are a host of enzymes in central carbon metabolism that act to combat reactive oxygen species (ROS) by directing the flow of glucose and glutamine carbon into defined metabolic pathways. Characterization of the metabolic circuit observed upon loss of FoxO3 revealed a drop in glutaminolysis and filling of the tricarboxylic acid (TCA) cycle. Additionally, we found that glucose uptake, glucose metabolism and oxidative pentose phosphate pathway activity were similarly repressed in the absence of FoxO3. Finally, we demonstrate that impaired glucose and glutamine metabolism compromises the proliferative potential of NPCs and that this is exacerbated following FoxO3 loss. Collectively, our findings show that a FoxO3-dependent metabolic programme supports redox balance and the neurogenic potential of NPCs.
    The EMBO Journal 09/2013; DOI:10.1038/emboj.2013.186 · 10.75 Impact Factor
  • Source
    • "During embryo development and in young mice (<3 weeks), the HSC compartment is continuously expanded, whereas HSC become largely quiescent in adult mice [27] [28]. These quiescent HSCs are less sensitive to replication-coupled DNA damage repair defects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The endonuclease complex Ercc1/Xpf is involved in interstrand crosslink repair and functions downstream of the Fanconi pathway. Loss of Ercc1 causes hematopoietic defects similar to those seen in Fanconi Anemia. Ercc1(-/-) mice die 3-4 weeks after birth, which prevents long-term follow up of the hematopoietic compartment. We used alternative Ercc1 mouse models to examine the effect of low or absent Ercc1 activity on hematopoiesis. Tie2-Cre-driven deletion of a floxed Ercc1 allele was efficient (>80%) in fetal liver hematopoietic cells. Hematopoietic stem and progenitor cells (HSPCs) with a deleted allele were maintained in mice up to 1 year of age when harboring a wt allele, but were progressively outcompeted when the deleted allele was combined with a knockout allele. Mice with a minimal Ercc1 activity expressed by 1 or 2 hypomorphic Ercc1 alleles have an extended life expectancy, which allows analysis of HSPCs at 10 and 20 weeks of age. The HSPC compartment was affected in all Ercc1-deficient models. Actively proliferating multipotent progenitors were most affected as were myeloid and erythroid clonogenic progenitors. In conclusion, lack of Ercc1 results in a severe competitive disadvantage of HSPCs and is most deleterious in proliferating progenitor cells.
    Anemia 06/2012; 2012:783068. DOI:10.1155/2012/783068
  • Source
    • "Our lab and others have shown that aging mouse HSCs show a decline long-term reconstituting potential (Chambers et al., 2007b; Rossi et al., 2007) and a deficit in lymphopoiesis (Sudo et al., 2000; Rossi et al., 2005). However, recent studies suggest that aging changes the clonal composition of the HSC compartment but does not alter the inherent properties of HSCs (Cho et al., 2008; Roeder et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The traditional view of hematopoiesis has been that all the cells of the peripheral blood are the progeny of a unitary homogeneous pool of hematopoietic stem cells (HSCs). Recent evidence suggests that the hematopoietic system is actually maintained by a consortium of HSC subtypes with distinct functional characteristics. We show here that myeloid-biased HSCs (My-HSCs) and lymphoid-biased HSCs (Ly-HSCs) can be purified according to their capacity for Hoechst dye efflux in combination with canonical HSC markers. These phenotypes are stable under natural (aging) or artificial (serial transplantation) stress and are exacerbated in the presence of competing HSCs. My- and Ly-HSCs respond differently to TGF-beta1, presenting a possible mechanism for differential regulation of HSC subtype activation. This study demonstrates definitive isolation of lineage-biased HSC subtypes and contributes to the fundamental change in view that the hematopoietic system is maintained by a continuum of HSC subtypes, rather than a functionally uniform pool.
    Cell stem cell 03/2010; 6(3):265-78. DOI:10.1016/j.stem.2010.02.002 · 22.15 Impact Factor
Show more


Available from