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

TitleGlucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo.
Publication TypeJournal Article
Year of Publication2013
AuthorsHarris, JM, Esain, V, Frechette, GM, Harris, LJ, Cox, AG, Cortes, M, Garnaas, MK, Carroll, KJ, Cutting, CC, Khan, T, Elks, PM, Renshaw, SA, Dickinson, BC, Chang, CJ, Murphy, MP, Paw, BH, Heiden, MGVander, Goessling, W, North, TE
JournalBlood
Volume121
Issue13
Pagination2483-93
Date Published2013 Mar 28
ISSN1528-0020
KeywordsAnimals, Animals, Genetically Modified, Carbohydrate Metabolism, Cell Proliferation, Embryo, Nonmammalian, Embryonic Induction, Gene Expression Regulation, Developmental, Glucose, Glycolysis, Hematopoiesis, Hematopoietic Stem Cells, Hypoxia-Inducible Factor 1, alpha Subunit, Oxidative Phosphorylation, Time Factors, Zebrafish
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 mitochondrial-derived reactive oxygen species (ROS)-mediated stimulation of hypoxia-inducible factor 1α (hif1α). Epistasis assays demonstrated that 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 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.

DOI10.1182/blood-2012-12-471201
Alternate JournalBlood
Citation Key10.1182/blood-2012-12-471201
PubMed ID23341543
PubMed Central IDPMC3612858
Grant List1R01DK090311 / DK / NIDDK NIH HHS / United States
5K01DK080226 / DK / NIDDK NIH HHS / United States
G0701932 / / Medical Research Council / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom
P01 HL032262 / HL / NHLBI NIH HHS / United States
R01 DK070838 / DK / NIDDK NIH HHS / United States