Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Institute of Biochemistry and Molecular Biology, Medical Faculty, University of Bonn, Bonn, North Rhine-Westphalia 53115, Germany.
Cell Stem Cell. 2021 Nov 4;28(11):1982-1999.e8. doi: 10.1016/j.stem.2021.07.011. Epub 2021 Aug 26.
The electron transport chain promotes aspartate synthesis, which is required for cancer cell proliferation. However, it is unclear whether aspartate is limiting in normal stem cells. We found that mouse hematopoietic stem cells (HSCs) depend entirely on cell-autonomous aspartate synthesis, which increases upon HSC activation. Overexpression of the glutamate/aspartate transporter, Glast, or deletion of glutamic-oxaloacetic transaminase 1 (Got1) each increased aspartate levels in HSCs/progenitor cells and increased the function of HSCs but not colony-forming progenitors. Conversely, deletion of Got2 reduced aspartate levels and the function of HSCs but not colony-forming progenitors. Deletion of Got1 and Got2 eliminated HSCs. Isotope tracing showed aspartate was used to synthesize asparagine and purines. Both contributed to increased HSC function as deletion of asparagine synthetase or treatment with 6-mercaptopurine attenuated the increased function of GLAST-overexpressing HSCs. HSC function is thus limited by aspartate, purine, and asparagine availability during hematopoietic regeneration.
电子传递链促进天冬氨酸的合成，这是癌细胞增殖所必需的。然而，目前尚不清楚天冬氨酸在正常干细胞中是否受到限制。我们发现，小鼠造血干细胞（HSCs）完全依赖于细胞自主的天冬氨酸合成，这种合成在 HSC 激活时增加。谷氨酸/天冬氨酸转运蛋白 Glast 的过表达或谷氨酸草酰乙酸转氨酶 1（Got1）的缺失都增加了 HSCs/祖细胞中天冬氨酸的水平，并增加了 HSCs 的功能，但不增加集落形成祖细胞的功能。相反，Got2 的缺失减少了 HSCs 中的天冬氨酸水平和功能，但不减少集落形成祖细胞。Got1 和 Got2 的缺失消除了 HSCs。同位素示踪表明天冬氨酸用于合成天冬酰胺和嘌呤。由于天冬酰胺合成酶的缺失或 6-巯基嘌呤的处理都削弱了 GLAST 过表达 HSCs 功能的增加，因此这两者都有助于增加 HSC 的功能。因此，在造血再生过程中，HSC 的功能受到天冬氨酸、嘌呤和天冬酰胺可用性的限制。
