Local Oxygen Tension Dictates Hematopoietic Cell Growth and Potency

Abstract

Hematopoietic stem and progenitor cells support a lifetime supply of blood and immune cells, can become neoplastic when dysregulated, and constitute a powerful cell therapy vehicle for hematologic diseases. Here we provide the most comprehensive study of hematopoietic oxygen (O2) dependency to date, demonstrating that human hematopoietic cell numbers, growth, biochemical properties, and functional potency is affected by variation in physiologically and clinically relevant local O2 tensions. Lineage defined progenitor cells showed increased expansion in high oxygen, while primitive cells and those with in vivo potency were maintained at higher frequencies in low physiologic O2. We also present a novel hematopoietic cell oxygen-dependent single cell transcriptomic profile. This and biochemical validation revealed that low O2 preserves cells with lower metabolic activity in a less proliferative state that exhibit decreased accumulation of stress markers. Transcriptomics and mouse modeling also elucidated oxygen-dependent mRNA markers of hematopoietic potency. These data reveal oxygen-sensing pathways as targets to improve hematopoietic cell therapies and suggest that local O2 tension dictates hematopoietic potential in anatomic niches.