Hematopoietic progenitor cell mobilization results in hypoxia with increased hypoxia-inducible transcription factor-1 alpha and vascular endothelial growth factor A in bone marrow.
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 showed by confocal laser scanning microscopy that the endosteum at the bone-BM interface is hypoxic, with constitutive expression of hypoxia-inducible transcription factor-1alpha (HIF-1alpha) protein in steady-state mice. Interestingly, at the peak of hematopoietic stem and progenitor cell (HSPC) mobilization induced by either granulocyte colony-stimulating factor or cyclophosphamide, hypoxic areas expand through the central BM. Furthermore, we found that HSPC mobilization leads to increased levels of HIF-1alpha protein and increased expression of vascular endothelial growth factor A (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 that occurs during mobilization depletes the BM hematopoietic microenvironment of O(2), leading to local hypoxia, stabilization of HIF-1alpha transcription factor in BM cells, increased transcription of VEGF-A, and accumulation of VEGF-A protein on BM sinuses that increases vascular permeability. Disclosure of potential conflicts of interest is found at the end of this article.
Lévesque
Jean-Pierre
JP
Mater Medical Research Institute, Raymond Terrace, Aubigny Place, South Brisbane, QLD, Australia. jplevesque@mmri.mater.org.au
Winkler
Ingrid G
IG
Hendy
Jean
J
Williams
Brenda
B
Helwani
Falak
F
Barbier
Valérie
V
Nowlan
Bianca
B
Nilsson
Susan K
SK
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D002199:Capillary Permeability / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D010101:Oxygen Consumption; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009593:Nitroimidazoles; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C033815:pimonidazole