TSC–mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species

By Chong Chen, Yu Liu, Runhua Liu, T. Ikenoue, Kunliang Guan, Yang Liu, P. Zheng. Journal of Experimental Medicine, 2008

677 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/9b40fe9bccf1b6f448512f74062a2f790136f18d

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In Immunology

1. David M. Sabatini
2. M. Laplante
3. G. Semenza

In Molecular Biology

1. M. Laplante
2. David M. Sabatini
3. G. Semenza
4. T. Suda
5. K. Takubo
6. C. V. Dang
7. Navdeep S. Chandel
8. B. Manning

In Physiology

1. T. Suda
2. David M. Sabatini
3. K. Takubo
4. M. Laplante
5. G. Semenza

Citations in the corpus

• mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells (2009, neutral): “Although Tsc1 deletion causes an immediate increase in HSC proliferation (17), self-renewal of the transplanted Tsc1 HSCs decreased over time (Fig.”
• Metabolic Plasticity in Stem Cell Homeostasis and Differentiation (2012, neutral): “Such mitochondrial infrastructure is also characteristic of hematopoietic stem cells (HSCs) (Piccoli et al., 2005) and mesenchymal stem cells (MSCs) (Chen et al., 2008b; Lonergan et al., 2006), Cell Stem Cell 11, November 2, 2012 ª2012 Elsevier Inc. 597 Catabolic and anabolic pathways are interconne”
• Metabolic regulation of hematopoietic stem cells in the hypoxic niche. (2011, background): “HSCs were no longer quiescent and lost reconstitution capacity (Chen et al., 2008; Gan et al., 2008).”
• The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance (2011, neutral): “Indeed, normal HSCs have relatively few mitochondria, and increased mitochondrial biogenesis has been demonstrated to trigger defective HSC maintenance (Kim et al., 1998; Chen et al., 2008).”
• mTOR signaling at a glance (2009, background): “…number, as well as the expression of many genes encoding proteins involved in oxidative metabolism, are reduced by rapamycin and increased by mutations that Journal of Cell Science 122 (20) Jo ur na l o f C el l S ci en ce 3591 activate mTORC1 signaling (Chen et al., 2008; Cunningham et al., 2007).”