Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 20, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI146272
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Funding
- National Natural Science Foundation of China [31971081, 31741085, 31800747]
- Tsinghua University Initiative Scientific Research Program
- Tsinghua-Peking Center for Life Sciences and Institute for Immunology at Tsinghua University
- Memorial Sloan Kettering Cancer Center Support Grant/Core Grant [P30 CA08748]
- [R01 AI 102888]
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This study demonstrates the critical role of nutrient mTORC1 signaling in maintaining hematopoietic stem cell (HSC) homeostasis. Loss of the mTORC1 regulators SZT2 and TSC1 leads to rapid HSC depletion and the synergistic effect of these losses significantly increases mTORC1 activity and ROS production, further depleting HSCs.
The mTORC1 pathway coordinates nutrient and growth factor signals to maintain organismal homeostasis. Whether nutrient signaling to mTORC1 regulates stem cell function remains unknown. Here, we show that SZT2 - a protein required for mTORC1 downregulation upon nutrient deprivation - is critical for hematopoietic stem cell (HSC) homeostasis. Ablation of SZT2 in HSCs decreased the reserve and impaired the repopulating capacity of HSCs. Furthermore, ablation of both SZT2 and TSC1 - 2 repressors of mTORC1 on the nutrient and growth factor arms, respectively - led to rapid HSC depletion, pancytopenia, and premature death of the mice. Mechanistically, loss of either SZT2 or TSC1 in HSCs led to only mild elevation of mTORC1 activity and reactive oxygen species (ROS) production. Loss of both SZT2 and TSC1, on the other hand, simultaneously produced a dramatic synergistic effect, with an approximately 10-fold increase of mTORC1 activity and approximately 100-fold increase of ROS production, which rapidly depleted HSCs. These data demonstrate a critical role of nutrient mTORC1 signaling in HSC homeostasis and uncover a strong synergistic effect between nutrient-and growth factor-mediated mTORC1 regulation in stem cells.
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