Chen Chong, Liu Yu, Liu Runhua, Ikenoue Tsuneo, Guan Kun-Liang, Liu Yang, Zheng Pan
Program of Cell and Developmental Biology, Division of Immunotherapy, Department of Surgery, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.
J Exp Med. 2008 Sep 29;205(10):2397-408. doi: 10.1084/jem.20081297. Epub 2008 Sep 22.
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.
结节性硬化症复合物（TSC）-雷帕霉素哺乳动物靶蛋白（mTOR）信号通路是细胞代谢的关键调节因子。我们通过条件性敲除Tsc1来研究静止状态与造血干细胞（HSC）功能之间的关联。我们证明，HSC中Tsc1的缺失会促使它们从静止状态进入快速循环，同时线粒体生物合成增加，活性氧（ROS）水平升高。重要的是，如连续和竞争性骨髓移植所示，这种缺失显著降低了HSC的造血能力和自我更新能力。用ROS拮抗剂进行体内治疗可恢复HSC的数量和功能。这些数据表明，TSC-mTOR信号通路通过抑制ROS生成来维持HSC的静止状态和功能。代谢活跃的HSC中ROS上调的有害作用可能解释了静止状态与HSC“干性”之间充分记录的关联。
