The aryl hydrocarbon receptor nuclear translocator is an essential regulator of murine hematopoietic stem cell viability

摘要

Hypoxia-inducible factors (HIFs) are master regulators of the transcriptional response to low oxygen and play essential roles in embryonic development, tissue homeostasis, and disease. Recent studies have demonstrated that hematopoietic stem cells (HSCs) within the bone marrow localize to a hypoxic niche and that HIF-1 alpha promotes HSC adaptation to stress. Because the related factor HIF-2 alpha is also expressed in HSCs, the combined role of HIF-1 alpha and HIF-2 alpha in HSC maintenance is unclear. To this end, we have conditionally deleted the HIF-alpha dimerization partner, the aryl hydrocarbon receptor nuclear translocator (ARNT) in the hematopoietic system to ablate activity of both HIF-1 alpha and HIF-2 alpha and assessed the functional consequence of ARNT deficiency on fetal liver and adult hematopoiesis. We determined that ARNT is essential for adult and fetal HSC viability and homeostasis. Importantly, conditional knockout of both HIF-1 alpha and Hif-2 alpha phenocopied key aspects of these HSC phenotypes, demonstrating that the impact of Arnt deletion is primarily HIF dependent. ARNT-deficient long-term HSCs underwent apoptosis, potentially because of reduced B-cell lymphoma 2 (BCL-2) and vascular endothelial growth factor A(VEGF-A) expression. Our results suggest that HIF activity may regulate HSC homeostasis through these prosurvival factors.