RRC ID 33667
著者 Harris 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, Vander Heiden MG, Goessling W, North TE.
タイトル Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo.
ジャーナル Blood
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.
巻・号 121(13)
ページ 2483-93
公開日 2013-3-28
DOI 10.1182/blood-2012-12-471201
PII S0006-4971(20)39453-2
PMID 23341543
PMC PMC3612858
MeSH 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
IF 17.794
引用数 60
WOS 分野 HEMATOLOGY
リソース情報
ゼブラフィッシュ Tg(EF1α:mKO2-zCdt1(1/190)/rw0405b Tg(EF1α:mAG-zGem(1/100)/rw0410h