Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo

James M. Harris, Virginie Esain, Gregory M. Frechette, Lauren J. Harris, Andrew G. Cox, Mauricio Cortes, Maija K. Garnaas, Kelli J. Carroll, Claire C. Cutting, Tahsin Khan, Philip M. Elks, Stephen A. Renshaw, Bryan C. Dickinson, Christopher J. Chang, Michael P. Murphy, Barry H. Paw, Matthew G. Vander Heiden, Wolfram Goessling, Trista E. North

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Many pathways regulating blood formation have been elucidated, yet how each coordinates with embryonic biophysiology to modulate the spatiotemporal 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 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 mitochondrialderived reactive oxygen species (ROS)-mediated stimulation of hypoxia-inducible factor 1a (hif1a). Epistasis assays demonstrated that hif1a regulates HSC formation in vivo and mediates the dose-dependent effects of glucose metabolism on the timing and magnitude of HSC production. We propose that 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.

Original languageEnglish (US)
Pages (from-to)2483-2493
Number of pages11
JournalBlood
Volume121
Issue number13
DOIs
StatePublished - 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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