Abstract 11441: Post Prandial Blood Glucose and Triglyceride Metabolism Govern Hematopoietic Stem Cell Transcriptional Regulation, Premature Aging and Rejuvenation

Hematopoietic stem cells (HSCs) have links to atherosclerotic cardiovascular disease through stem cell-mediated endothelial repair and clonal hematopoiesis (CH) with myeloid-biased differentiation. Previous reports showed that type 2 diabetes (T2DM) or aging decays stem cell-mediated endothelial rep...

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Veröffentlicht in:Circulation (New York, N.Y.) N.Y.), 2019-11, Vol.140 (Suppl_1 Suppl 1), p.A11441-A11441
Hauptverfasser: Horitani, Keita, Iwasaki, Masayoshi, Kishimoto, Hiroshi, Wada, Kensaku, Shiojima, Ichiro
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Sprache:eng
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Zusammenfassung:Hematopoietic stem cells (HSCs) have links to atherosclerotic cardiovascular disease through stem cell-mediated endothelial repair and clonal hematopoiesis (CH) with myeloid-biased differentiation. Previous reports showed that type 2 diabetes (T2DM) or aging decays stem cell-mediated endothelial repair and is closely related to CH. Although recent HSC research revealed that HSC metabolism dictates whether HSCs proliferate, differentiate or remain quiescent, mechanistic link between HSC behavior and impaired metabolism in T2DM is not clear. In this study, we asked how the metabolism in T2DM affects HSC behavior. First, we carried out clinical study and found that postprandial hyperglycemia at 60 minutes showed the best correlation with the number of circulating HSC (r=-0.534), and the coexistence of postprandial hypertriglyceridemia further improved the correlation (r=-0.534→-0.691). We therefore examined the effect of repetitive postprandial glucose/triglyceride spikes on bone marrow cell (BMC) by injecting glucose/lipid emulsion in C57BL/6 mice for 7 days. Mice experimental study revealed that repetitive glucose+lipid spikes (GLs), but not repetitive glucose spikes (Gs) or lipid spikes (Ls), induced premature aging phenotype of BMC, i.e. impaired HSC quiescence and function, and myeloid-biased differentiation. It is well known that quiescent HSCs rely on glycolysis and restrict mitochondrial oxidative phosphorylation (OXPHOS). On the other hand, proliferative HSCs augment OXPHOS. Subsequent analysis showed that the regulation of mitochondrial gate keeping in response to Gs plays a pivotal role for the maintenance of HSC quiescence and function, and that GLs hampered it. RNA sequence analysis with Ingenuity Pathway Analysis revealed that Gs and GLs quite differentially affected HSC transcriptional regulation. HSCs activated HIF1α and further restricted OXPHOS in response to Gs. On the other hand, GLs activated p53 and PTEN in HSCs and augmented OXPHOS. GLs also activated the earliest myeloid transcriptional program in HSCs. We also confirmed that the cessation of GLs rejuvenated BMC. Our study showed that postprandial blood glucose and triglyceride govern HSC transcription, metabolism, premature aging and rejuvenation.
ISSN:0009-7322
1524-4539
DOI:10.1161/circ.140.suppl_1.11441