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

Abstract

• Glucose metabolism enhances hematopoietic stem cell formation and function in the vertebrate embryo • Glucose metabolism modulates hif1a activity via mitochondrial generation of reactive oxygen species to impact HSC-relevant gene expressionMany 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. (Blood. 2013;121(13):2483-2493

Stem cells and the impact of ROS signaling

“…They also support the notion that, in ESCs, the need for glycolysis meets the biosynthetic demands of highly proliferative cells, similar to the Warburg effect in cancer cells (Ward and Thompson, 2012). Interestingly, glucose metabolism increases the generation of hematopoietic stem cells via ROSmediated HIF stabilization, a mechanism that might be implicated in leukemia in children exposed to high glucose in general (Harris et al, 2013;Hjalgrim et al, 2004).…”

“…the emergence of embryonic blood stem cells or differentiation of embryonic cardiomyocytes (Harris et al, 2013;Hernández-García et al, 2010;Hom et al, 2011). There is also increasing evidence that ROS are implicated at many distinct levels of biological processes, from gene expression and protein translation to protein-protein interactions, etc.…”

Stem Cells, Redox Signaling, and Stem Cell Aging

“…Importantly, ROS directly regulate the function of a number of proteins implicated in stress response and metabolism (see Table 1). Recent findings describe a physiological function for ROS in the control of disease and developmental processes (33,35,78,89) further supporting a key function for ROS in cellular signaling in vivo.…”

“…Although such studies have reached new heights within the past decade, the basis for the ability of deeply quiescent cells to proliferate on demand is not known. Several recent publications point to metabolism as a potential source for resolving this enigma (35,110,129).…”

“…ROS are being increasingly implicated in the physiological regulation of critical developmental processes, including the emergence of embryonic blood stem cells (33,35,89). A potential model may be that ROS function as a stem cell rheostat by sensing and translating environmental cues into a cellular response to balance cellular output (function) with cellular input (e.g., nutrients, cytokines).…”