Glucose metabolism impacts the spatio-temporal onset and magnitude of HSC induction in vivo

Harris, J.M., Esain, V., Frechette, G.M., Harris, L.J., Cox, A.G., Cortes, M., Garnaas, M.K., Carroll, K.J., Cutting, C.C., Khan, T., Elks, P.M., Renshaw, S.A., Dickinson, B.C., Chang, C.J., Murphy, M.P., Paw, B.H., Vander Heiden, M.G., Goessling, W., and North, T.E.
Blood   121(13): 2483-2493 (Journal)
Registered Authors
Elks, Phil, Garnaas, Maija, Goessling, Wolfram, Harris, James, North, Trista, Paw, Barry, Renshaw, Steve A.
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Carbohydrate Metabolism/genetics
  • Carbohydrate Metabolism/physiology*
  • Cell Proliferation/drug effects
  • Embryo, Nonmammalian
  • Embryonic Induction*/drug effects
  • Embryonic Induction*/genetics
  • Gene Expression Regulation, Developmental
  • Glucose/metabolism*
  • Glucose/pharmacology
  • Glycolysis/drug effects
  • Glycolysis/genetics
  • Glycolysis/physiology
  • Hematopoiesis/drug effects
  • Hematopoiesis/genetics
  • Hematopoiesis/physiology
  • Hematopoietic Stem Cells/cytology
  • Hematopoietic Stem Cells/drug effects
  • Hematopoietic Stem Cells/metabolism
  • Hematopoietic Stem Cells/physiology*
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit/physiology
  • Oxidative Phosphorylation
  • Time Factors
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
23341543 Full text @ Blood

Many pathways regulating blood formation have been elucidated, yet how each coordinates with embryonic biophysiology to modulate the spatio-temporal production of hematopoietic stem cells (HSCs) is currently unresolved. Here, we report that glucose metabolism impacts the onset and magnitude of HSC induction in vivo. In zebrafish, transient elevations in physiological glucose levels elicited dose-dependent effects on HSC development, including enhanced runx1 expression and hematopoietic cluster formation in the Aorta-Gonad-Mesonephros (AGM) region; embryonic-to-adult transplantation studies confirmed glucose increased functional HSCs. Glucose uptake was required to mediate the enhancement in HSC development; likewise, metabolic inhibitors diminished nascent HSC production and reversed glucose-mediated effects on HSCs. Increased glucose metabolism preferentially impacted hematopoietic and vascular targets, as determined by gene expression analysis, through mitochondrial-derived reactive oxygen species (ROS)-mediated stimulation of hypoxia inducible factor 1α (hif1α); epistasis assays demonstrated hif1α regulates HSC formation in vivo and mediates the dose-dependent effects of glucose metabolism on the timing and magnitude of HSC production. We propose this fundamental metabolic-sensing mechanism enables the embryo to respond to changes in environmental energy input and adjust hematopoietic output to maintain embryonic growth and ensure viability.

Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes