Aspartate Is Limiting for Hematopoietic Stem Cell Function in vivo

A key function of the electron transport chain is to promote aspartate synthesis, which is required for cancer cell proliferation. However, it is unclear whether aspartate is also limiting in normal stem cells, which divide intermittently. We found that hematopoietic stem cells (HSCs) do not take up exogenous aspartate. To test if aspartate limits HSC function, we over-expressed the glutamate/aspartate transporter, Glast, or deleted glutamic-oxaloacetic transaminase 1 (Got1). Each increased aspartate levels in hematopoietic stem/progenitor cells, increasing the function of HSCs but not colony-forming progenitors. Conversely, deletion of glutamic-oxaloacetic transaminase 2 (Got2) reduced aspartate levels and HSC function but not colony-forming progenitors. Isotope tracing showed aspartate was used to synthesize asparagine and purines. Both contributed to increased HSC function as deletion of asparagine synthetase (Asns) or treatment with 6-mercaptopurine attenuated the increased function of GLAST over-expressing HSCs. Stem cell function is thus limited by aspartate in some contexts.