1. Metabolic Regulation of Hematopoietic Stem Cells in the Hypoxic Niche
Toshio Suda, Keiyo Takubo, Gregg L. Semenza 
Cell Stem Cell 
Volume 9, Issue 4, Pages (October 2011)
DOI: /j.stem
Copyright © 2011 Elsevier Inc. Terms and Conditions

2. Figure 1 Differentiation of Hematopoietic Stem Cells
Long-term hematopoietic stem cells (LT-HSCs) are at the top of the hematopoietic hierarchy and are classified into two states, quiescent and cycling. LT-HSCs produce short-term (ST)-HSCs followed by multipotent progenitors (MPPs), lineage-restricted progenitors, and terminally differentiated hematopoietic cells.
Cell Stem Cell 2011 9, DOI: ( /j.stem )
Copyright © 2011 Elsevier Inc. Terms and Conditions

3. Figure 2 Stem Cell Defense Mechanisms and Potential Stress Responses
Bulleted points indicate stem cell properties that confer stem cell resistance to various cytotoxic insults. After the cellular stress exposure, the fate of a cell is survival, senescence, cell death, premature differentiation, or oncogenic transformation.
Cell Stem Cell 2011 9, DOI: ( /j.stem )
Copyright © 2011 Elsevier Inc. Terms and Conditions

4. Figure 3 HIF-1α Function in HSCs
(A) Shown is a representation of HIF-1α protein and interacting regulatory factors. HIF-1α is a substrate for both prolyl and asparaginyl hydroxylases. Under normoxia, proline and asparagine residues are hydroxylated by specific dioxygenases, modifications that regulate their stability and transcriptional activity. bHLH, basic-helix-loop-helix domain; PAS, Per-ARNT-Sim domain; TAD-N, transactivation domain N-terminal; ID, inhibitory domain; TAD-C, C-terminal transactivation domain; PHD, prolyl hydroxylase domain-containing protein; and FIH-1, factor-inhibiting HIF-1.
(B) Schematic representation of outcomes following HIF-1α or VHL deletion in HSCs.
Cell Stem Cell 2011 9, DOI: ( /j.stem )
Copyright © 2011 Elsevier Inc. Terms and Conditions

5. Figure 4 Stabilization of HIF-1α Protein after Hypoxic Exposure
Immunocytochemical detection of HIF-1α (green), FoxO3a (red), and c-Kit (gray) in HSCs (CD34− LSK cells) exposed to 12 hr of hypoxia (right) or normoxia (left) without cytokines. Preferential stabilization of HIF-1α was observed in HSCs under hypoxia (modified from Takubo et al., 2010).
Cell Stem Cell 2011 9, DOI: ( /j.stem )
Copyright © 2011 Elsevier Inc. Terms and Conditions

6. Figure 5 Metabolic Pathways in Central Carbon Metabolism
(A) Extracellular glucose is taken up by cells and subjected to glycolysis (blue area), the pentose phosphate pathway (orange area), or the TCA cycle (green area). G6P, glucose-6-phosohate; F6P, fructose-6-phosphate; F1,6BP, fructose-1,6-bisphosphate; DHAP, dihydroxyacetone phosphate; 1,3-BPG, 1,3-bisphosphoglyceric acid; 2,3-BPG, 2,3-bisphosphoglyceric acid; 3-PG, 3-phosphoglycerate; PEP, phosphoenolpyruvate; 6PG, 6-phosphogluconate; Ru5P, ribulose 5-phosphate; R5P, ribose 5-phosphate; S7P, sedoheptulose 7-phosphate; E4P, erythrose 4-phosphate.
(B) IDH mutations or TET deficiency results in abnormal hematopoiesis. Wild-type mitochondrial IDH2 catalytically converts Iso-citrate to 2-OG in the TCA cycle. Mutated IDH2 (IDH2mut) and cytoplasmic IDH1 (IDH1mut) proteins acquire a new catalytic activity to convert 2-OG to 2-HG. 2-HG inhibits several histone demethylases and the TET1 and TET2 hydroxymethylases and stabilizes HIF-1α. In HSCs these alterations result in DNA hypermethylation, enhanced self-renewal, and myeloproliferation. IDH1, isocitrate dehydrogenase 1; IDH2, isocitratedehyrogenase 2; 2-OG, 2-oxoglutarate; 2-HG, 2-hydroxyglutarate; HIF-1α, hypoxia-inducible factor 1 alpha; TET1, Tet oncogene family member 1; TET2, Tet oncogene family member 2.
Cell Stem Cell 2011 9, DOI: ( /j.stem )
Copyright © 2011 Elsevier Inc. Terms and Conditions

7. Figure 6 HSC Signaling Pathways Governing Quiescence and Cycling
The PI3K/Akt pathway is activated under conditions of high oxygen or high nutrients, an activity accompanied by enhanced protein synthesis, oxidative phosphorylation, and ROS generation. Overactivation of the Akt pathway exhausts HSCs through a ROS-independent manner. Quiescent HSCs maintain low ROS levels via several systems, including promotion of glycolysis and autophagy, and upregulation of FoxO proteins. Lkb1 may facilitate HSC maintenance through distinct mechanisms.
Cell Stem Cell 2011 9, DOI: ( /j.stem )
Copyright © 2011 Elsevier Inc. Terms and Conditions