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Lim, Sung-Eun

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Lim

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Sung-Eun

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Lim, Sung-Eun

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    Metabolic Regulation of Hematopoietic Stem Cell Production and Maintenance
    (2016-06-20) Lim, Sung-Eun; Paw, Barry; Galloway, Jenna; Feng, Hui
    Metabolic disorders are a leading cause of morbidity and mortality, with gestational diabetes impacting embryogenesis. Intriguingly, children born to diabetic mothers have a higher risk of developing childhood leukemia, suggesting increased blood sugar concentrations may have lasting hematological impact. Hematopoietic stem cells (HSCs), born during embryogenesis, are capable of both self-renewal and differentiation into mature blood cell types for the life of an organism; yet, the impact of glucose elevation on hematopoietic system development is unclear. We recently showed transient glucose elevation elicited dose-dependent effects on HSCs through metabolic stimulation and subsequent ROS-mediated induction of Hypoxia Inducible Factor-1α (Hif1α). Platelet Derived Growth Factor-B (pdgfb), a Hif1α-target, and its receptor, pdgfrb, were significantly upregulated in response to metabolic induction. Morpholino (MO) knockdown of pdgfrb blocked HSC elevation by Hif1α-stimulation as determined by in situ hybridization (WISH) for conserved HSC markers runx1 and cmyb; similar results were observed for the pan-PDGF inhibitor AG1295 and PDGFRβ-selective modifier DMPQ. Notably, overexpression of pdgfb enhanced runx1 expression in the AGM at 36hpf and cmyb in the CHT at 48hpf. A qRT-PCR survey of PDGF-B/PDGFRβ regulatory targets revealed a significant increase in IL-6 and its receptor (IL-6R). MO-mediated knockdown of il6 antagonized effects of pdgfb overexpression, while epistatic analysis indicated function downstream of Hif1α. Together, these findings define a Hif1α-regulated signaling axis acting via PDGFRβ and IL-6/IL-6R to control HSPC production. In contrast to responses to moderate flux in metabolic rate, chronic embryonic glucose elevation caused hematologic abnormalities, including elevated erythrocyte and myeloid cell numbers, with decreased lymphoid production, as seen by WISH, qPCR, and FACS. This is due in part to Hif1α-mediated transcriptional regulation, as determined by exposure to the Hif1 antagonist YC1. Interestingly, ablation of islet cell-mediated insulin production antagonized myeloid lineage dysregulation. Further, phosphorylation of FOXOs1/3/4, downstream targets of insulin signaling, was increased in glucose treated embryos. Microarray analysis of CD41:GFP+ HSCs from embryos exposed to chronic glucose elevation identified a number of putative pathways contributing to lineage dysregulation. Together, these studies indicate both acute and chronic alterations in metabolic state affect HSCs and may further explain immunological phenotypes associated with gestational diabetes.