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¹ Program of Cell and Developmental Biology, ² Division of Immunotherapy, Department of Surgery, ³ Department of Internal Medicine, ⁴ Department of Pathology, and ⁵ Life Science Institute, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor, MI 48109
⁶ Department of Pharmacology and Cancer Center, University of California, San Diego, La Jolla, CA 92093

CORRESPONDENCE Pan Zheng: panz{at}umich.edu OR Yang Liu: yangl{at}umich.edu

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.

© 2008 Chen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• Inoki, K., Guan, K.-L. (2009). Tuberous sclerosis complex, implication from a rare genetic disease to common cancer treatment. Hum Mol Genet 18: R94-R100 [Abstract] [Full Text]  
• Chen, C., Liu, Y., Liu, R., Ikenoue, T., Guan, K.-L., Liu, Y., Zheng, P. (2008). TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. JCB 183: i1-i1 [Full Text]  

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