期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 205, 期 10, 页码 2397-2408出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20081297
关键词
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资金
- National Institutes of Health
- United States Department of Defense
- American Cancer Society
- University of Michigan Comprehensive Cancer Center
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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