Local oxygen tension dictates hematopoietic cell growth and potency

Hematopoietic stem and progenitor cells support a lifetime supply of blood and immune cells and constitute a powerful cell therapy platform for hematologic diseases. In this study, we define oxygen-dependent activities of hematopoietic stem and progenitor cells. We found that lineage-defined progenitor cells from umbilical cord blood, bone marrow, and mobilized peripheral blood showed increased expansion in high oxygen, while primitive cells- including those from cord blood with in vivo potency- were maintained at higher frequencies in low physiologic O₂. Single cell transcriptomic profiling of hematopoiesis under varying oxygen revealed the expected modulation of molecular hypoxia programs, including HIF and MTORc signaling. Transcriptomics also identified genes that are understudied in the context of oxygen dependency including MDM4 pathway and PRSS2, which we found is an mRNA biomarker for hematopoietic cell potency. Transcriptional changes together with biochemical validation revealed that low oxygen preserves cells with lower metabolic activity in a less proliferative state that exhibit decreased accumulation of stress markers. This likely occurs via dynamic interplay of multiple molecular programs and may drive differences in cell potency. Collectively, these data identify oxygen-sensing pathways as targets to improve cell therapies and suggest that local oxygenation dictates hematopoietic potential in anatomic niches.