TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species.
TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species.
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DOI：
10.1084/jem.20081297
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发表时间：
2008-09-29
期刊：
影响因子：
--
通讯作者：
Zheng P
中科院分区：
文献类型：
--
作者：
Chen C;Liu Y;Liu R;Ikenoue T;Guan KL;Liu Y;Zheng P
结节性硬化症复合物（TSC）-雷帕霉素靶蛋白（mTOR）通路是细胞代谢的关键调节因子。我们通过条件性敲除Tsc1来探究静息状态与造血干细胞（HSCs）功能之间的关联。我们证明，造血干细胞中Tsc1的缺失使其从静息状态进入快速循环，伴有线粒体生物发生增加以及活性氧（ROS）水平升高。重要的是，正如连续和竞争性骨髓移植所揭示的，这种缺失显著降低了造血作用以及造血干细胞的自我更新能力。体内使用一种活性氧拮抗剂治疗可恢复造血干细胞的数量和功能。这些数据表明，TSC - mTOR通路通过抑制活性氧的产生来维持造血干细胞的静息状态和功能。在代谢活跃的造血干细胞中活性氧上调的有害影响或许可以解释静息状态与造血干细胞“干性”之间已被充分证明的关联。
The tuberous sclerosis complex (TSC)–mammalian target of rapamycin (mTOR) pathway is a key regulator of cellular metabolism. We used conditional deletion of Tsc1 to address how quiescence is associated with the function of hematopoietic stem cells (HSCs). We demonstrate that Tsc1 deletion in the HSCs drives them from quiescence into rapid cycling, with increased mitochondrial biogenesis and elevated levels of reactive oxygen species (ROS). Importantly, this deletion dramatically reduced both hematopoiesis and self-renewal of HSCs, as revealed by serial and competitive bone marrow transplantation. In vivo treatment with an ROS antagonist restored HSC numbers and functions. These data demonstrated that the TSC–mTOR pathway maintains the quiescence and function of HSCs by repressing ROS production. The detrimental effect of up-regulated ROS in metabolically active HSCs may explain the well-documented association between quiescence and the “stemness” of HSCs.
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