SZT2 maintains hematopoietic stem cell homeostasis via nutrient-mediated mTORC1 regulation
Na Yin, … , Ming O. Li, Min Peng
Na Yin, … , Ming O. Li, Min Peng
Published October 17, 2022
Citation Information: J Clin Invest. 2022;132(20):e146272. https://doi.org/10.1172/JCI146272.
View: Text | PDF
Research Article Hematology Metabolism

SZT2 maintains hematopoietic stem cell homeostasis via nutrient-mediated mTORC1 regulation

Abstract

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.

Authors

Na Yin, Gang Jin, Yuying Ma, Hanfei Zhao, Guangyue Zhang, Ming O. Li, Min Peng

×

Figure 1

SZT2 is essential for the repopulating potential of HSCs.

Options: View larger image (or click on image) Download as PowerPoint
SZT2 is essential for the repopulating potential of HSCs. (A) A diagram ...
(A) A diagram of BM chimera experiment. WT (CD45.1/45.2) and VavCreSzt2fl/fl (SZT2-KO; CD45.2) BM cells were mixed at 1:1 ratio and injected into lethally irradiated CD45.1 recipient mice. Chimerism was monitored. (B) Blood chimerism of recipient mice at indicated time points. n = 7 mice per genotype, P < 0.0001 (2-way ANOVA). Data shown are representative of 4 independent experiments. (C and D) Chimerism of blood, spleen (SPL) and BM at 19 weeks after transplantation. Representative plots (C) and statistics (D) are shown. Data shown are representative of 2 independent experiments. (E and F) Frequencies of B cells (B220+), T cells (B220–CD11b–CD4+/CD8+) and myeloid cells (CD11b+) derived from WT or SZT2-KO BM. Representative plots (E) and summary data (F) are shown. (G and H) The contribution of WT and SZT2-KO BM to the Lin–c-Kit+Sca-I+ (LSK) population at 19 weeks after transplantation. Representative plots (G) and quantification (H) are shown. Data shown are representative of 2 independent experiments. In D, F, and H, data represent mean ± SEM, n = 7 mice per genotype, ****P < 0.0001 (paired 2-tailed t test.