Hypoxia regulates the hematopoietic stem cell niche

Bone marrow, the site of hematopoiesis throughout adulthood, is a physiologically hypoxic organ. Thus, various biological oxygen sensors and their signaling cascades play a pivotal role in hematopoietic systems in the bone marrow under both physiologic and pathologic conditions. Hypoxia-inducible factors (HIFs) are hypoxic stress sensor proteins that are stabilized under homeostatic or stress-induced hypoxia. In the hypoxic bone marrow, HIFs play crucial roles in hematopoietic stem cells (HSCs) and in the cells of the HSC niche. The signals downstream of the HIFs maintain HSC quiescence, survival, and metabolic homeostasis through both cell-autonomous and non-cell-autonomous mechanisms. Leukemic stem cells (LSCs) hijack these delicate hypoxia-sensing mechanisms to sustain their self-renewal potential, promoting disease progression and drug resistance even under normoxic conditions. This review focuses on HIF-mediated oxygen-sensing mechanisms of adult HSCs and LSCs and their niche cells in the hypoxic bone marrow.