Metabolic regulation of hematopoietic stem cell specification and function

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DESCRIPTION (provided by applicant): Metabolic disorders, including obesity and diabetes, are the leading cause of preventable death in the U.S. The incidence of gestational diabetes has similarly increased. The impact of physiologically elevated glucose levels on hematopoiesis is not established. Hematopoietic stem cells (HSCs) are essential for survival, as they function to produce each of the mature blood cell lineages throughout the lifespan of the organism. The first HSCs arise from hemogenic endothelium in the aorta-gonad-mesonephros (AGM) region. Most genes involved in HSC formation, such as RUNX1, are highly conserved across vertebrates, and continue to regulate HSC homeostasis in the adult. We have successfully used zebrafish to identify novel regulators of vertebrate HSCs, resulting in the first FDA-approved clinical trial originating from zebrafish studies. To assess the impact of metabolic regulation on HSCs, we exposed zebrafish embryos to increasing physiological doses of glucose and observed that elevated glucose levels enhanced the timing and magnitude of embryonic HSC formation. Our long-term goal is to characterize the impact of nutrient availability on HSC formation and function. Our objective here is to characterize the effects of modulation of glucose metabolism on HSC induction, proliferation and differentiation in the vertebrate embryo. Our central hypothesis is that glucose- metabolism impacts HSC formation via production of ROS and subsequent hif1α stabilization to drive coordinate expression of hematopoietic genes. The rationale for our work is that an understanding of the impact of physiological glucose fluctuations on HSCs will elucidate potential risks of dysregulated metabolism on the hematopoietic system, which has long-term consequences for immunity. In Specific Aim 1, we will assess the impact of excess glucose on the spatio-temporal onset and progression of HSC development. Using chemical and genetic modulation of metabolism, we will identify the mechanism by which glucose impacts HSC-related transcriptional regulation via hif1α. Our preliminary data show physiological glucose elevation significantly accelerates HSC induction. In Specific Aim 2, we will assess the impact of acute versus chronic hyperglycemia and coordinated hif1α target gene regulation on HSC function. We will confirm the evolutionary conservation of these effects in an adult injury model, murine gestational diabetes models and in human umbilical cord blood. Our preliminary data indicate glucose exposure enhances recovery after marrow injury and hif1α activity in the AGM and placenta correlates with HSC production, suggesting glucose metabolism is a conserved regulatory factor. The expected outcomes of this proposal are a detailed understanding of the spatio-temporal dynamics and molecular mechanisms of glucose metabolism-mediated HSC regulation. These results will provide insight into how the developing organism senses and responds to fluctuations in nutrient supply to match hematopoietic output with anticipated growth rates, and will have a direct impact on our understanding of the risks of gestational diabetes on hematopoiesis and for therapeutic HSC modulation.