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

By T. Şimşek, Fatih Kocabaş, Junke Zheng, Ralph J. Deberardinis, A. Mahmoud, E. Olson, J. Schneider, C. Zhang, Hesham A. Sadek. Cell Stem Cell, 2010

1,061 citations recorded by the source corpus.

SUMMARY 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-1α are markedly enriched in LT-HSCs and that Meis1 regulates HSC metabolism through transcriptional activation of Hif-1α. These findings reveal an important transcriptional network that regulates HSC metabolism.

Subfields: Cancer Research, Hematology, Immunology

View Paper: https://www.semanticscholar.org/paper/8eb189036f286a7fb4d847c1993a251cb18790ae

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. G. Semenza
2. Richard J. Johnson
3. T. Suda
4. Benjamin L. Ebert
5. J. Dick
6. K. Takubo
7. C. V. Dang
8. M. C. Simon

In Hematology

1. G. Semenza
2. T. Suda
3. Benjamin L. Ebert
4. J. Dick
5. K. Takubo

In Immunology

1. Mihai G. Netea
2. L. Joosten
3. G. Semenza
4. Marc Beyer
5. Richard J. Johnson
6. Joachim L. Schultze
7. J. Dick
8. G. Hajishengallis

Citations in the corpus

• Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury. (2015, positive): “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).”
• Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. (2013, background): “LT-HSCs, which exhibit fewer mitochondria than progenitors (Kim et al., 1998; Simsek et al., 2010; Norddahl et al., 2011), are hypothesized to utilize anaerobic metabolism in the hypoxic endosteal zone.”
• Metabolic regulation of hematopoietic stem cells in the hypoxic niche. (2011, background): “It would be interesting to know whether treatment with a p38 MAPK inhibitor reverses senescence in HSCs. p16Ink4a and p19Arf are encoded by the Ink4a/Arf locus. p16Ink4a causes Rb hypophosphorylation by inhibiting CDK4/6 activity, and suppresses E2F-dependent gene expression.”
• Stem cell gene expression programs influence clinical outcome in human leukemia (2011, background): “Genes shared in our LSC and HSC expression profiles such as MECOM , MEIS1 , HOXB3 and ERG are key regulators of normal murine and/or human HSC functio”
• BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells (2013, background): “Interestingly, ROS-low subsets isolated from the M9-ENL1 AML cell line and from normal marrow CD34+ cells were also more quiescent as compared to corresponding ROS-high cells (Figure S1E), indicating that the association between lower ROS and quiescence is conserved in both cell lines and normal HSC”
• Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity (2018, background): “LT-HSCs depend on glycolysis for their maintenance (Simsek et al., 2010; Takubo et al., 2013; Wang et al., 2014), whereas the activation of OXPHOS is associated with their functional impairment, loss of self-renewal potential, and induction of DNA damage (Suda et al., 2011; Takizawa et al., 2017;…”
• Metabolic Plasticity in Stem Cell Homeostasis and Differentiation (2012, positive): “In fact, the majority of LT-HSCs can be metabolically sorted by gating for low mitochondrial membrane potential and low endogenous NADH fluorescence, and were shown to have greater capacity for in vitro colony formation and in vivo bone marrow reconstitution (Simsek et al., 2010).”