Hematopoietic Progenitor Cell Mobilization Results in Hypoxia with Increased HIF-1 and VEGF-A in Bone Marrow

¹ Mater Medical Research Institute, South Brisbane, Queensland, Australia; University of Queensland, Brisbane, Queensland, Australia
² Mater Medical Research Institute, South Brisbane, Queensland, Australia
³ Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
⁴ Australian Stem Cell Centre, Monash University, Clayton, Victoria, Australia
⁵ Australian Stem Cell Centre, Monash University, Clayton, Victoria, Australia; Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia

^* To whom correspondence should be addressed. E-mail: jplevesque{at}mmri.mater.org.au.

	Abstract

Despite the fact that many hypoxia-inducible genes are important in hematopoiesis, the spatial distribution of oxygen in the bone marrow (BM) has not previously been explored in vivo. Using the hypoxia bioprobe pimonidazole, we show by confocal laser scanning microscopy that the endosteum at the bone-BM interface is hypoxic with constitutive expression of hypoxia-inducible transcription factor-1 (HIF-1) protein in steady-state mice. Interestingly, at the peak of hematopoietic stem and progenitor cell (HSPC) mobilization induced by either G-CSF or cyclophosphamide (CY), hypoxic areas expand through the central BM. Furthermore, we found that HSPC mobilization leads to increased levels of HIF-1 protein and increased expression of VEGF-A mRNA throughout the BM, with an accumulation of VEGF-A protein in BM endothelial sinuses. VEGF-A is a cytokine known to induce stem cell mobilization, vasodilatation and vascular permeability in vivo. We therefore propose that the expansion in myeloid progenitors which occurs during mobilization, depletes O₂ from the BM hematopoietic microenvironment, leading to local hypoxia, stabilization of HIF-1 transcription factor in BM cells, increased transcription of VEGF-A, and accumulation of VEGF-A protein on BM sinuses that increases vascular permeability.

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