Showed why blood stem cells must keep mTOR LOW. Deleting TSC1 (which unleashes mTOR) drove resting stem cells into rapid division, flooded them with reactive oxygen species, and burned out their ability to self-renew. An antioxidant rescued them. A key link between mTOR, stem-cell exhaustion, and tissue aging.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Mouse (conditional Tsc1 knockout) |
| Journal | Journal of Experimental Medicine |
| Year | 2008 |
| Peer reviewed | Yes |
| Source | DOI 10.1084/jem.20081297 · PMID 18809716 · Free full text (PMC2556783) |
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.
| Intervention | Genetic (Tsc1 conditional knockout) |
| Target | TSC-mTOR / mitochondrial biogenesis / ROS |
| Model | Mouse (conditional Tsc1 KO) |
| Effect | TSC-mTOR maintains hematopoietic stem cell quiescence and function by repressing mitochondrial biogenesis and ROS |