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

TLDR

The TSC–mTOR pathway is a key regulator of cellular metabolism. The study used conditional deletion of Tsc1 to investigate how quiescence relates to hematopoietic stem cell function. Conditional deletion of Tsc1 in HSCs was performed, showing that loss of Tsc1 drives cells from quiescence into rapid cycling, increasing mitochondrial biogenesis and reactive oxygen species. Tsc1 deletion reduced hematopoiesis and self‑renewal, but ROS antagonist treatment restored HSC numbers and function, proving that TSC–mTOR maintains HSC quiescence and function by repressing ROS and linking quiescence to stemness.

Abstract

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.