Harnessing Hematopoietic Stem Cell Low Intracellular Calcium Improves Their Maintenance In Vitro

The specific cellular physiology of hematopoietic stem cells (HSCs) is underexplored, and their maintenance in vitro remains challenging. We discovered that culture of HSCs in low calcium increased their maintenance as determined by phenotype, function, and single-cell expression signature. HSCs are endowed with low intracellular calcium conveyed by elevated activity of glycolysis-fueled plasma membrane calcium efflux pumps and a low-bone-marrow interstitial fluid calcium concentration. Low-calcium conditions inhibited calpain proteases, which target ten-eleven translocated (TET) enzymes, of which TET2 was required for the effect of low calcium conditions on HSC maintenance in vitro. These observations reveal a physiological feature of HSCs that can be harnessed to improve their maintenance in vitro. Maintenance of blood stem cells in vitro remains challenging. Snoeck and colleagues show that blood stem cells are endowed with low intracellular calcium and that culture in low-calcium media enhances their maintenance, among others, through stabilization of TET enzymes, which are required for normal stem cell function.