Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Shinano-machi, Shinjuku-ku, Tokyo, Japan.
Cell Stem Cell. 2013 Jan 3;12(1):49-61. doi: 10.1016/j.stem.2012.10.011.
Defining the metabolic programs that underlie stem cell maintenance will be essential for developing strategies to manipulate stem cell capacity. Mammalian hematopoietic stem cells (HSCs) maintain cell cycle quiescence in a hypoxic microenvironment. It has been proposed that HSCs exhibit a distinct metabolic phenotype under these conditions. Here we directly investigated this idea using metabolomic analysis and found that HSCs generate adenosine-5'-triphosphate by anaerobic glycolysis through a pyruvate dehydrogenase kinase (Pdk)-dependent mechanism. Elevated Pdk expression leads to active suppression of the influx of glycolytic metabolites into mitochondria. Pdk overexpression in glycolysis-defective HSCs restored glycolysis, cell cycle quiescence, and stem cell capacity, while loss of both Pdk2 and Pdk4 attenuated HSC quiescence, glycolysis, and transplantation capacity. Moreover, treatment of HSCs with a Pdk mimetic promoted their survival and transplantation capacity. Thus, glycolytic metabolic status governed by Pdk acts as a cell cycle checkpoint that modulates HSC quiescence and function.
定义干细胞维持所依赖的代谢程序对于开发操纵干细胞能力的策略至关重要。哺乳动物造血干细胞 (HSC) 在低氧微环境中保持细胞周期静止。有人提出，在这些条件下，HSC 表现出独特的代谢表型。在这里，我们使用代谢组学分析直接研究了这一想法，发现 HSC 通过丙酮酸脱氢酶激酶 (Pdk)-依赖性机制通过无氧糖酵解产生腺苷-5'-三磷酸。Pdk 表达水平的升高导致糖酵解代谢物进入线粒体的通量被积极抑制。在糖酵解缺陷的 HSC 中过表达 Pdk 可恢复糖酵解、细胞周期静止和干细胞能力，而 Pdk2 和 Pdk4 的缺失则减弱了 HSC 静止、糖酵解和移植能力。此外，用 Pdk 模拟物处理 HSC 可促进其存活和移植能力。因此，由 Pdk 控制的糖酵解代谢状态作为细胞周期检查点，调节 HSC 静止和功能。
