The role of the TSC -mTOR pathway on the regulation of the hematopoietic stem cells

The hematopoietic stem cells (HSCs) constitute a small population of cells in the bone marrow, responsible for the maintenance of the hematopoietic and lymphatic systems over the lifespan. Most adult hematopoietic stem cells (HSCs) are quiescent under stable conditions. It has been suggested that quiescence is critical for maintaining the long-term functions of HSCs. However it is still unclear why quiescence is required for the stemness. In this study, we identified the TSC-mTOR pathway as a novel regulator of the quiescence and functions of HSCs. Deletion of Tsc1, a negative regulator of mTOR, leads to the loss of quiescence and rapid cell cycle of HSCs, resulting in an expanded HSC pool. However, Tsc1 mutant HSCs had cell-intrinsic defects, including dramatically reduced regenerative capacity demonstrated by transplant, which also lead to severe bone marrow failure and abnormal hematogenesis in Tsc1 deficient mice. We found that reactive oxygen species (ROS) was downstream target of mTOR for the regulation of HSC. Hyperactive mTOR signaling enhanced the mitochondrial biogenesis and the production of ROS in HSCs. Removal of ROS by NAC treatment rescued the reconstitution capacity of Tsc1 deficient HSCs. Our data suggest a link between quiescence and stemness that quiescence is the strategy for HSCs to avoid the accumulation of toxic reactive oxygen species (ROS) generated by high level of mitochondrial metabolism activities during division.;The dysregulation of the mTOR pathway was also found in different physiological and pathological conditions. mTOR signaling was hyperactivated in HSCs over age. Inhibition of mTOR by rapamycin significantly improved the regenerative capacity of the aged HSCs and enhanced the generation of lymphoid cells. HSCs from LPS-triggered sepsis mice and the scurfy mice with autoimmune diseases display functional defects measured by transplant, associated with hyperactive mTOR pathway. Rapamycin treatment prevented the loss of reconstitution capacity of HSCs induced by these pathological conditions. We conclude that the mTOR pathway is essential for the regulation of HSCs and that mTOR hyperactivation is the underlying cause of HSC defects in aging, autoimmune diseases and sepsis, which suggests new approaches for restoring HSC function in aging, sepsis and autoimmune diseases.