Chinese scholars have discovered a new mechanism for maintaining hematopoietic stem cell homeostasis

Figure Schematic diagram of the key role mechanism of nutritional regulation of mTORC1 in hematopoietic stem cell homeostasis

With the support of the National Natural Science Foundation of China (grant numbers: 31971081, 31741085), the team of Associate Professor Peng Min of Tsinghua University revealed the key
protein SZT2 of mammalian target of rapamycin complex (mTORC) in maintaining hematopoietic stem cell homeostasis 。 The research results, titled "SZT2 maintains hematopoietic stem cell homeostasis via nutrient-mediated mTORC1 regulation", were published in The Journal of Clinical Research on October 17, 2022 Investigation)
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Nutrition is the material basis of life activities, and the energy required for the growth, development, homeostasis and reproduction of organisms comes from nutrients in food
.
Overnutrition is closely related to the occurrence and development of many diseases, including obesity, diabetes, tumors, etc
.
The mTORC1 signaling pathway plays a key role
in sensing nutritional signals and maintaining homeostasis.
mTORC1 activity is regulated by both growth factors and nutrition, and although the mechanism of growth factors regulating mTORC1 through PI3K-AKT has been thoroughly studied, the molecular mechanism of how nutrients regulate mTORC1 is not fully understood
.

The TSC complex (TSC1/TSC2) deletion mouse model is a standard animal model that simulates mTORC1 overactivation, mainly simulating the overactivation
of mTORC1 by growth factors 。 Due to the central role of SZT2 in the negative regulation of nutrient induction and mTORC1, conditioned SZT2-deficient mice were used to simulate the high activity of mTORC1 caused by excessive nutrition in vivo, and it was found that bone marrow-derived blood cells of SZT2-deficient mice after bone marrow reconstruction decreased rapidly in the peripheral blood of wild-type recipient mice, suggesting that SZT2 is particularly important
for maintaining the regenerative ability of hematopoietic stem cells (HSCs).
In SZT2 and TSC1 double-knockout mice, simultaneous deletion of SZT2 and TSC1 resulted in rapid HSC depletion, pancytopenia, and premature death
in mice.
Further molecular biology studies showed that the deletion of SZT2 or TSC1 alone resulted in only a mild increase in mTORC1 activity and reactive oxygen species (ROS) of HSCs, while simultaneous deletion of SZT2 and TSC1 produced a significant synergistic effect, with an approximately 10-fold increase in mTORC1 activity and approximately 100-fold increase in ROS production, rapidly depleting HSCs (Figure).

By analyzing the significant synergistic effects of nutrition and growth factor regulation mTORC1 in the maintenance of homeostasis in hematopoietic stem cells, this study suggests that excessive nutrition and overactivation of growth factors can deplete hematopoietic stem cells and thus endanger the maintenance
of homeostasis.