Hypoxia Regulates Lymphoid Development of Human Hematopoietic Progenitors

Summary Hypoxia plays a major role in the physiology of hematopoietic and immune niches. Important clues from works in mouse have paved the way to investigate the role of low O2 levels in hematopoiesis. However, whether hypoxia impacts the initial steps of human lymphopoiesis remains unexplored. Here, we show that hypoxia regulates cellular and metabolic profiles of umbilical cord blood (UCB)-derived hematopoietic progenitor cells. Hypoxia more specifically enhances in vitro lymphoid differentiation potentials of lymphoid-primed multipotent progenitors (LMPPs) and pro-T/natural killer (NK) cells and in vivo B cell potential of LMPPs. In accordance, hypoxia exacerbates the lymphoid gene expression profile through hypoxia-inducible factor (HIF)-1α (for LMPPs) and HIF-2α (for pro-T/NK). Moreover, loss of HIF-1/2α expression seriously impedes NK and B cell production from LMPPs and pro-T/NK. Our study describes how hypoxia contributes to the lymphoid development of human progenitors and reveals the implication of the HIF pathway in LMPPs and pro-T/NK-cell lymphoid identities.