Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration

Le Qi, Misty S. Martin-Sandoval, Salma Merchant, Wen Gu, Matthias Eckhardt, Thomas P. Mathews, Zhiyu Zhao, Michalis Agathocleous, Sean J. Morrison

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1982-1999.e8
JournalCell Stem Cell
Volume28
Issue number11
DOIs
StatePublished - Nov 4 2021

Keywords

  • asparagine
  • aspartate
  • electron transport chain
  • hematopoietic stem cell
  • metabolism
  • mitochondria
  • purine
  • regeneration

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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