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

Bryan L. Krock, Tzipora S. Eisinger-Mathason, Dionysios N. Giannoukos, Jessica E. Shay, Mercy Gohil, David S. Lee, Michael S. Nakazawa, Julie Sesen, Nicolas Skuli, M. Celeste Simon

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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-1α promotes HSC adaptation to stress. Because the related factor HIF-2α is also expressed in HSCs, the combined role of HIF-1α and HIF-2α in HSC maintenance is unclear. To this end, we have conditionally deleted the HIF-α dimerization partner, the aryl hydrocarbon receptor nuclear translocator (ARNT) in the hematopoietic system to ablate activity of both HIF-1α and HIF-2α 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-1α and Hif-2α 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.

Original languageEnglish (US)
Pages (from-to)3263-3272
Number of pages10
JournalBlood
Volume125
Issue number21
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • Arnt promotes adult hematopoietic stem cell viability through regulation of bcl-2 and vegf-a expression
  • Fetal liver hematopoietic progenitors experience hypoxia and loss of hypoxiainduced transcription decreases their survival

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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