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

Abstract

A long-standing but poorly understood observation in stem cell biology is that the quiescence of the adult stem cells associates with their longterm functions ( 1 -6 ). The molecular pathway that keeps them in quiescence is largely obscure, although recent studies have implicated stem cell niches ( 4 ) and cell-intrinsic functions of p21 ( 5 ) and Pten ( 6 ) in this process. The signifi cance of quiescence in stem cell function is bolstered as genetic disruption of its quiescence almost invariably inactivates the hematopoietic stem cell (HSC) function ( 4 -6 ). Nevertheless, it is largely unclear how an active metabolism is incompatible with a normal HSC function.In addition to cell-intrinsic factors, accumulating data demonstrated that residence of adult HSCs in the BM niches is essential for their quiescence and long-term functions ( 7 -9 ). Because exposure to high levels of oxygen damages the functions of HSCs ( 10 -15 ), it has been proposed that hypoxia is important for HSC functions. However, the underlying molecular mechanism of how hypoxia maintains the stemness is unknown.In Drosophila and in vitro -cultured mammalian cells, hypoxia activates tuberous sclerosis complex (TSC), which can inhibit the target of rapamycin (TOR), through REDD1 and AMP-activated protein kinase ( 16 -20 ). Whether this pathway operates in the HSCs has yet to be tested.The mammalian TOR (mTOR) pathway has emerged as a key regulator for cellular metabolism. Accumulating data have demonstrated that mTOR regulates several important cellular functions, including protein synthesis, autophagy, endocytosis and nutrient uptake ( 21 ). An increased mTOR activity results in increased cellular growth and nonmalignant growth of cells in solid organs ( 22,23 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.

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…In contrast, other studies have suggested roles for ROS in depletion of TSC1-deficient HSCs. 186 In these studies, TSC-1 depletion causes mTOR activation, exit from quiescence, increased proliferation, but leads to exhaustion of HSCs without the development of leukemia.…”

Cell cycle regulation in hematopoietic stem cells

“…Interestingly, pretreatment of aged mice with rapamycin, which inhibits mTOR activity, rescues many of the functional defects observed in old HSCs, including their decreased cell cycle activity and diminished engraftment . At the moment it is quite challenging to integrate this observation with the aforementioned increase in p16 Ink4a expression exhibited by the old HSCs because increased mTOR activity results in increased HSC cycling, at least in young Pten / and Tsc1 / HSCs (Yilmaz et al, 2006;C. Chen et al, 2008).…”

“…As described previously, mouse models that lead to unchecked levels of mTOR activity result in a deregulated HSC compartment and stem cell exhaustion (Yilmaz et al, 2006;Zhang et al, 2006;C. Chen et al, 2008).…”

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

“…Therefore, retaining functional TSC1/2‐mTORC1 regulation may be beneficial for certain cancer cells (Mieulet & Lamb, 2010). An important role of TSC1/2 in metabolic homeostasis was revealed in hematopoietic stem cells (HSCs) where deletion of TSC1 results in elevated mTORC1 activity and increased ROS production with detrimental effects on HCS function and survival (Chen et al , 2008). A database survey revealed that TSC1 ‐mRNA expression is the highest in Burkitt's lymphoma‐derived cell lines compared to 36 different tumor‐type cell lines in the Cancer Cell Line Encyclopedia (CCLE; http://www.broadinstitute.org/ccle) (Fig EV1A).…”