Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration.
Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration.
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DOI：
10.1016/j.stem.2021.07.011
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发表时间：
2021-11-04
期刊：
影响因子：
23.9
通讯作者：
Morrison SJ
中科院分区：
文献类型：
--
作者：
Qi L;Martin-Sandoval MS;Merchant S;Gu W;Eckhardt M;Mathews TP;Zhao Z;Agathocleous M;Morrison SJ
电子传递链促进天冬氨酸的合成，而天冬氨酸是癌细胞增殖所必需的。然而，天冬氨酸在正常干细胞中是否受到限制尚不清楚。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，而天冬氨酸合成在HSC激活后增加。谷氨酸/天冬氨酸转运体Glast的过度表达或谷草转氨酶1(GOT1)的缺失均可增加造血干/祖细胞中的天冬氨酸水平，并增强HSCs的功能，但不能促进集落形成。相反，谷草转氨酶2(Got2)的缺失降低了天冬氨酸水平和造血干细胞的功能，但不会减少集落形成的祖细胞。GOT1和Got2基因缺失消除了HSCs。同位素示踪表明，天冬氨酸被用于合成天冬酰胺和嘌呤。两者均导致肝星状细胞功能增强，因为天冬酰胺合成酶的缺失或6-巯基嘌呤处理减弱了过表达GLAST的肝星状细胞的功能增强。因此，在造血再生过程中，肝星状细胞的功能受到天冬氨酸、嘌呤和天冬酰胺供应的限制。线粒体功能促进天冬氨酸的合成，天冬氨酸是蛋白质和核苷酸的关键组成部分。莫里森和他的同事表明，造血干细胞完全依赖细胞自主合成的天冬氨酸，而HSC的功能受到天冬氨酸可获得性的限制。在再生过程中，肝星状细胞增加天冬氨酸的合成，从而通过增加天冬氨酸和嘌呤的合成促进肝星状细胞的功能。
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. Over-expression of the glutamate/aspartate transporter, Glast, or deletion of glutamic-oxaloacetic transaminase 1 (Got1) each increased aspartate levels in hematopoietic stem/progenitor cells and increased the function of HSCs but not colony-forming progenitors. Conversely, deletion of glutamic-oxaloacetic transaminase 2 (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 over-expressing HSCs. HSC function is thus limited by aspartate, purine, and asparagine availability during hematopoietic regeneration. Mitochondrial function promotes aspartate synthesis, a critical building block for proteins and nucleotides. Morrison and colleagues show hematopoietic stem cells depend exclusively on cell-autonomously synthesized aspartate and HSC function is limited by aspartate availability. During regeneration, HSCs increase aspartate synthesis, which promotes HSC function by increasing asparagine and purine synthesis.
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影响因子：
21.3
作者：
Flores A;Schell J;Krall AS;Jelinek D;Miranda M;Grigorian M;Braas D;White AC;Zhou JL;Graham NA;Graeber T;Seth P;Evseenko D;Coller HA;Rutter J;Christofk HR;Lowry WE
通讯作者：
Lowry WE
DOI：
10.1084/jem.20161087
发表时间：
2017-03-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Guitart AV;Panagopoulou TI;Villacreces A;Vukovic M;Sepulveda C;Allen L;Carter RN;van de Lagemaat LN;Morgan M;Giles P;Sas Z;Gonzalez MV;Lawson H;Paris J;Edwards-Hicks J;Schaak K;Subramani C;Gezer D;Armesilla-Diaz A;Wills J;Easterbrook A;Coman D;So CW;O'Carroll D;Vernimmen D;Rodrigues NP;Pollard PJ;Morton NM;Finch A;Kranc KR
通讯作者：
Kranc KR
影响因子：
4.1
作者：
ATKINSON, MR;MURRAY, AW;MORTON, RK
通讯作者：
MORTON, RK
影响因子：
5.2
作者：
Baris, Olivier R.;Klose, Anke;Wiesner, Rudolf J.
通讯作者：
Wiesner, Rudolf J.
MDH1介导的苹果酸-天冬氨酸NADH穿梭维持胎儿肝脏造血干细胞的活性水平
影响因子：
20.3
作者：
Gu, Hao;Chen, Chiqi;Zheng, Junke
通讯作者：
Zheng, Junke