The Distinct Metabolic Profile of Hematopoietic Stem Cells Reflects Their Location in a Hypoxic Niche

Department of Internal Medicine, Division of Cardiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Cell stem cell (Impact Factor: 22.27). 09/2010; 7(3):380-90. DOI: 10.1016/j.stem.2010.07.011
Source: PubMed

ABSTRACT Bone marrow transplantation is the primary therapy for numerous hematopoietic disorders. The efficiency of bone marrow transplantation depends on the function of long-term hematopoietic stem cells (LT-HSCs), which is markedly influenced by their hypoxic niche. Survival in this low-oxygen microenvironment requires significant metabolic adaptation. Here, we show that LT-HSCs utilize glycolysis instead of mitochondrial oxidative phosphorylation to meet their energy demands. We used flow cytometry to identify a unique low mitochondrial activity/glycolysis-dependent subpopulation that houses the majority of hematopoietic progenitors and LT-HSCs. Finally, we demonstrate that Meis1 and Hif-1alpha are markedly enriched in LT-HSCs and that Meis1 regulates HSC metabolism through transcriptional activation of Hif-1alpha. These findings reveal an important transcriptional network that regulates HSC metabolism.

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    • "Class III genes, which include many NSC/astrocyte markers (e.g., Nr2e1, Hes5, Fabp7 [Blbp], Aldh1l1, Slc1a3, and Slc1a2), were enriched for genes involved in glycolysis. We find that expression of these genes is highest in qNSCs and already lower in aNSCs, suggesting that glycolytic metabolism is a defining feature of qNSCs, similar to quiescent stem cells in the hematopoietic system (Simsek et al., 2010). The decrease of glial-associated genes in aNSCs compared to qNSCs suggests that the glial gene-expression program starts to be shut down at the aNSC level, presumably to initiate the acquisition of neuronal fate. "
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    ABSTRACT: Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell stem cell 07/2015; 17(3). DOI:10.1016/j.stem.2015.07.002 · 22.27 Impact Factor
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    • "This actively maintained quiescence is important for long-term functionality of stem cells. Quiescent stem cells have minimal basal metabolic activity, contain only few mitochondria and rely mainly on glycolysis for their energy production [46] [47]. Even though mitochondria are few and mitochondrial respiration is low, stem cells contain a functional respiratory chain. "
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    ABSTRACT: Decline in metabolism and regenerative potential of tissues are common characteristics of aging. Regeneration is maintained by somatic stem cells (SSCs), which require tightly controlled energy metabolism and genomic integrity for their homeostasis. Recent data indicate that mitochondrial dysfunction may compromise this homeostasis, and thereby contribute to tissue degeneration and aging. Progeroid Mutator mouse, accumulating random mtDNA point mutations in their SSCs, showed disturbed SSC homeostasis, emphasizing the importance of mtDNA integrity for stem cells. The mechanism involved changes in cellular redox-environment, including subtle increase in reactive oxygen species (H2O2 and superoxide anion), which did not cause oxidative damage, but disrupted SSC function. Mitochondrial metabolism appears therefore to be an important regulator of SSC fate determination, and defects in it in SSCs may underlie premature aging. Here we review the current knowledge of mitochondrial contribution to SSC dysfunction and aging. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 05/2015; DOI:10.1016/j.bbabio.2015.05.014 · 4.66 Impact Factor
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    • "These cells were able to maintain their functional properties after prolonged storage in anoxia in vitro and after transplantation (Latil et al., 2012). Similarly, it has been shown that several stem cell populations reside in poorly oxygenated niches (Simsek et al., 2010). Quiescent stem cells have the ability to sense environmental changes and respond by re-entering the cell cycle for proliferation (Cheung and Rando, 2013). "
    Frontiers in Physiology 03/2015; 6. DOI:10.3389/fphys.2015.00099 · 3.53 Impact Factor
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