Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. James M. Harris1,
  2. Virginie Esain1,
  3. Gregory M. Frechette1,
  4. Lauren J. Harris1,
  5. Andrew G. Cox2,
  6. Mauricio Cortes1,
  7. Maija K. Garnaas2,
  8. Kelli J. Carroll1,
  9. Claire C. Cutting2,
  10. Tahsin Khan3,
  11. Phillip M. Elks4,
  12. Stephen A. Renshaw4,
  13. Bryan C. Dickinson5,
  14. Christopher J. Chang5,
  15. Michael P. Murphy6,
  16. Barry H. Paw7,
  17. Matthew G. Vander Heiden8,
  18. Wolfram Goessling9, and
  19. Trista E. North1,*
  1. 1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States;
  2. 2 Genetics and Gastroenterology Divisions, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States;
  3. 3 Koch Institute, Massachusetts Institute of Technology, Cambridge, MA, United States;
  4. 4 MRC Centre for Developmental and Biomedical Genetics, Sheffield, United Kingdom;
  5. 5 Department of Chemistry and Howard Hughes Medical Institute, University of California Berkeley, CA, United States;
  6. 6 MRC Mitochondrial Biology Unit, Cambridge, United Kingdom;
  7. 7 Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States;
  8. 8 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States;
  9. 9 Harvard Stem Cell Institute, Cambridge, MA, United States
  1. * Corresponding author; email: tnorth{at}

Key points

  • Glucose metabolism enhances hematopoietic stem cell formation and function in the vertebrate embryo

  • Glucose metabolism modulates hif1α activity via mitochondrial generation of ROS to impact HSC-relevant gene expression


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.

  • Submitted December 5, 2012.
  • Accepted January 14, 2013.