SZT2 maintains hematopoietic stem cell homeostasis via nutrient-mediated mTORC1 regulation Journal Article
| Authors: | Yin, N.; Jin, G.; Ma, Y.; Zhao, H.; Zhang, G.; Li, M. O.; Peng, M. |
| Article Title: | 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. © 2022, Yin et al. |
| Keywords: | adult; controlled study; survival rate; genetics; nonhuman; flow cytometry; protein function; cd8 antigen; animal cell; mouse; animal; metabolism; animals; mice; apoptosis; bone marrow; spleen; steady state; animal experiment; genotype; transcription factor; enzyme activity; cell population; phosphorylation; b lymphocyte; chimera; blood analysis; hamartin; hematopoietic stem cells; reactive oxygen species; reactive oxygen metabolite; cell count; down regulation; pancytopenia; bone marrow cell; hematopoietic stem cell; cd4 antigen; nutrient; homeostasis; bone marrow transplantation; growth factor; stem cell niche; sirolimus; genomic dna; lethality; cell stress; depletion; repressor gene; antibody conjugate; mammalian target of rapamycin complex 1; protein s6; exhaustion; seizure threshold; synergistic effect; nutrients; fluorescence intensity; article; mechanistic target of rapamycin complex 1; alexa fluor 647; seizure threshold 2 |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 132 |
| Issue: | 20 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2022-10-17 |
| Start Page: | e146272 |
| Language: | English |
| DOI: | 10.1172/jci146272 |
| PUBMED: | 36250465 |
| PROVIDER: | scopus |
| PMCID: | PMC9566891 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
