Article

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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Available from: Fatih Kocabas, Nov 20, 2015
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    • "Previous studies reported that surface marker CD49b (Integrin a2) could further separate conventional LT-HSCs (CD34 À Flk2 À Lineage À Sca- 1 + c-Kit + [LSK]) into CD49b lo LT-HSCs that maintain permanent reconstituting ability and CD49b hi intermediate-term (IT)-HSCs that support only 6–8 months of multipotent hematopoiesis (Benveniste et al., 2010). Recent studies reported that metabolic properties are required for maintenance of different states of HSCs (Suda et al., 2011; Takubo et al., 2013), and a low mitochondrial potential correlates with HSC functionality (Simsek et al., 2010). How cell-cycle status and metabolic states are precisely controlled in HSCs remains largely unknown. "
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    ABSTRACT: The mammalian imprinted Dlk1-Gtl2 locus produces multiple non-coding RNAs (ncRNAs) from the maternally inherited allele, including the largest miRNA cluster in the mammalian genome. This locus has characterized functions in some types of stem cell, but its role in hematopoietic stem cells (HSCs) is unknown. Here, we show that the Dlk1-Gtl2 locus plays a critical role in preserving long-term repopulating HSCs (LT-HSCs). Through transcriptome profiling in 17 hematopoietic cell types, we found that ncRNAs expressed from the Dlk1-Gtl2 locus are predominantly enriched in fetal liver HSCs and the adult LT-HSC population and sustain long-term HSC functionality. Mechanistically, the miRNA mega-cluster within the Dlk1-Gtl2 locus suppresses the entire PI3K-mTOR pathway. This regulation in turn inhibits mitochondrial biogenesis and metabolic activity and protects LT-HSCs from excessive reactive oxygen species (ROS) production. Our data therefore show that the imprinted Dlk1-Gtl2 locus preserves LT-HSC function by restricting mitochondrial metabolism.
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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.
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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). "

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