Impaired Vascular Oxygen Sensing Affects the Maintainance and Regeneration of the Bone Marrow

Abstract

Hypoxia provides critical cues in specialized niches that sustain stem cells. The bone marrow (BM) stem cell niche is a highly hypoxic microenvironment known to support hematopoietic stem and progenitor cells (HSPCs). These cells reside in anatomical vascular sub‐compartments within the bone marrow whereby the quiescent hematopoietic cells (HSCs) are found near arterioles in the endosteal zone while the more proliferative hematopoietic progenitor cells (HPCs) occupy the perivascular niche zone containing specialized fenestrated sinusoidal endothelial cells (SECs). Using an inducible genetic system, we conditionally inactivated the required HIF­β subunit [Aryl hydrocarbon receptor nuclear translocator (ARNT)] of Hypoxia Inducible Factor (HIF) in the endothelium in the vasculature of 8‐ week old mice (ArntiΔEC) to understand its transcriptional role in directing the maintenance of the BM stem cell niche. We observe that compromised endothelium of ArntiΔEC mice results in a distinct disturbance to the BM's vascular microenvironment. Following 5‐Fluorouracil (5‐FU) treatment, ArntiΔEC mice experience myelodysplasia, impaired BM revascularization and regeneration. There is a reduction in proangiogenic transcript levels in RNA isolated from bone marrow's of 5‐FU myeloablated ArntiΔEC mice. Lethal levels of γ‐irradiation result in hematopoietic failure and death of ArntiΔEC mice as transplanted control BM cells fail to engraft and reconstitute their bone marrow. These results support our hypothesis that endothelial‐HIF is required for orchestrating the maintenance and regeneration of the vasculature in the bone marrow's stem cell niche in response to stress.