mTORC1 signaling governs hematopoietic stem cell quiescence

Abstract

The stringent regulation of hematopoietic stem cell (HSC) quiescence versus cell cycle progression is essential for the preservation of a pool of long-term self-renewing cells and vital for sustaining an adequate supply of all blood lineages throughout life. Cell growth, the process that is mass increase, serves as a trigger for cell cycle progression and is regulated predominantly by mammalian target of rapamycin complex 1 (mTORC1) signaling. Emerging data from various mice models show deletion of several mTORC1 negative regulators, including PTEN, TSC1, PML and Fbxw7 result in similar HSC phenotypes characterized as HSC hyper-proliferation and subsequent exhaustion, and defective repopulating potential. Further pharmacological approaches show that PTEN, TSC1 and PML regulate HSC maintenance through mTORC1. mTORC1-mediated cell growth regulatory circuits thus play a critical role in the regulation of HSC quiescence.

Figrure 1. mTORC1-mediated cell growth machinery in the regulation of hematopoietic stem cell quiescence

mTORC1 functions to integrates various upstream signaling pathways to regulate protein synthesis and cell growth. mTORC1 hyper-activation resulting from inactivation of PTEN, TSC1, PML and potentially Fbxw7 (all highlighted in box), drives HSC from quiescent state and leads to subsequent HSC exhaustion. Akt promotes mTORC1 activation and inhibits FoxO transcriptional factors. FoxOs (highlighted in box) function to maintain HSC quiescence through suppression of reactive oxygen species (ROS). For simplicity and for the focus of this review, several components of mTORC1 pathway, such as AMPK, REDD1, are not shown in this figure.