Cited2 Is Required for the Maintenance of Glycolytic Metabolism in Adult Hematopoietic Stem Cells
Cited2 Is Required for the Maintenance of Glycolytic Metabolism in Adult Hematopoietic Stem Cells
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DOI：
10.1089/scd.2013.0370
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发表时间：
2014-01-15
影响因子：
4
通讯作者：
Yang, Yu-Chung
中科院分区：
文献类型：
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作者：
Du, Jinwei;Li, Qiang;Yang, Yu-Chung
哺乳动物成年造血干细胞（hsc）存在于缺氧的骨髓微环境中，与其祖细胞相比显示出不同的代谢表型。有人提出造血干细胞主要通过丙酮酸脱氢酶激酶（Pdk）依赖的厌氧糖酵解产生能量。Cited2是HSC静止、凋亡和功能的重要调节因子。本研究表明，小鼠造血干细胞中Cited2的条件缺失导致活性氧水平升高，细胞谷胱甘肽含量降低，线粒体活性增加，糖酵解减少。在分子水平上，Cited2缺乏显著降低了参与代谢的基因的表达，如Pdk2、Pdk4和乳酸脱氢酶B和D （LDHB和LDHD）。cited2缺失的造血干细胞也表现出Akt信号的增加，同时mTORC1活性和FoxOs磷酸化升高。此外，抑制PI3/Akt，而不是mTORC1，部分地恢复了Cited2缺失引起的Pdk4的抑制。总之，我们的研究结果表明，Cited2可能是通过调节Pdk2、Pdk4、LDHB、LDHD和Akt活性来维持成人HSC糖酵解代谢所必需的。
Mammalian adult hematopoietic stem cells (HSCs) reside in the hypoxic bone marrow microenvironment and display a distinct metabolic phenotype compared with their progenitors. It has been proposed that HSCs generate energy mainly through anaerobic glycolysis in a pyruvate dehydrogenase kinase (Pdk)-dependent manner. Cited2 is an essential regulator for HSC quiescence, apoptosis, and function. Herein, we show that conditional deletion of Cited2 in murine HSCs results in elevated levels of reactive oxygen species, decreased cellular glutathione content, increased mitochondrial activity, and decreased glycolysis. At the molecular level, Cited2 deficiency significantly reduced the expression of genes involved in metabolism, such as Pdk2, Pdk4, and lactate dehydrogenases B and D (LDHB and LDHD). Cited2-deficient HSCs also exhibited increased Akt signaling, concomitant with elevated mTORC1 activity and phosphorylation of FoxOs. Further, inhibition of PI3/Akt, but not mTORC1, partially rescued the repression of Pdk4 caused by deletion of Cited2. Altogether, our results suggest that Cited2 is required for the maintenance of adult HSC glycolytic metabolism likely through regulating Pdk2, Pdk4, LDHB, LDHD, and Akt activity.