Distinct roles of Rheb and Raptor in activating mTOR complex 1 for the self-renewal of hematopoietic stem cells

Abstract The mammalian target of rapamycin (mTOR) complex 1 ( mTORC1) senses a cell's energy status and environmental levels of nutrients and growth factors. In response, mTORC1mediates signaling that controls protein translationand cellular metabolism. Although mTORC1plays a critical role in hematopoiesis, it remains unclear which upstream stimuli regulate mTORC1activity in the context of hematopoietic stem cells (HSC) maintenance in vivo . In this study, we investigated the function of Rheb, a critical regulator of mTORC1activity controlled by the PI3K-AKT-TSC axis, both in HSC maintenance in mice at steady-state and in HSC-derived hematopoiesis post-transplantation. In contrast to the severe hematopoietic dysfunction caused by Raptor deletion, which completely inactivates mTORC1, Rhebdeficiency in adult mice did not show remarkable hematopoietic failure. Lack of Rhebcaused abnormalities in myeloid cells but did not have impact on hematopoietic regeneration in mice subjected to injury by irradiation. As previously reported, Rhebdeficiency resulted in defective HSC-derived hematopoiesis post-transplantation. However, while Raptor is essential for HSC competitiveness in vivo , Rhebis dispensable for HSC maintenance under physiological conditions, indicating that the PI3K-AKT-TSC pathway does not contribute to mTORC1activity for sustaining HSC self-renewal activity at steady-state. Thus, the various regulatory elements that impinge upstream of mTORC1activation pathways are differentially required for HSC homeostasis in vivo.