Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration

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. [Display omitted] •Hematopoietic stem cells (HSCs) depend exclusively on the aspartate they synthesize•Aspartate synthesis in HSCs increases during hematopoietic regeneration•HSC function is limited by aspartate availability during hematopoietic regeneration•Aspartate increases HSC function by increasing asparagine and purine synthesis Mitochondrial function promotes aspartate synthesis, a critical building block for proteins and nucleotides. Qi and colleagues show that hematopoietic stem cells depend exclusively on cell-autonomously synthesized aspartate and that HSC function is limited by aspartate availability. During regeneration, HSCs increase aspartate synthesis, which promotes HSC function by increasing asparagine and purine synthesis.