title: Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo.
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.
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors: James M
authors: JM
authors: Harris
authors: Virginie
authors: V
authors: Esain
authors: Gregory M
authors: GM
authors: Frechette
authors: Lauren J
authors: LJ
authors: Harris
authors: Andrew G
authors: AG
authors: Cox
authors: Mauricio
authors: M
authors: Cortes
authors: Maija K
authors: MK
authors: Garnaas
authors: Kelli J
authors: KJ
authors: Carroll
authors: Claire C
authors: CC
authors: Cutting
authors: Tahsin
authors: T
authors: Khan
authors: Philip M
authors: PM
authors: Elks
authors: Stephen A
authors: SA
authors: Renshaw
authors: Bryan C
authors: BC
authors: Dickinson
authors: Christopher J
authors: CJ
authors: Chang
authors: Michael P
authors: MP
authors: Murphy
authors: Barry H
authors: BH
authors: Paw
authors: Matthew G
authors: MG
authors: Vander Heiden
authors: Wolfram
authors: W
authors: Goessling
authors: Trista E
authors: TE
authors: North
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D050260:Carbohydrate Metabolism / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004625:Embryo, Nonmammalian; D004627:Embryonic Induction / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology; D010085:Oxidative Phosphorylation; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D005947:Glucose