HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2006-0688v1 25/8/1954    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lévesque, J.-P. Articles by Nilsson, S. K. Search for Related Content PubMed PubMed Citation Articles by Lévesque, J.-P. Articles by Nilsson, S. K.

THE STEM CELL NICHE

Hematopoietic Progenitor Cell Mobilization Results in Hypoxia with Increased Hypoxia-Inducible Transcription Factor-1 and Vascular Endothelial Growth Factor A in Bone Marrow

^aMater Medical Research Institute, South Brisbane, Queensland, Australia;
^bUniversity of Queensland, Brisbane, Queensland, Australia;
^cPeter MacCallum Cancer Centre, East Melbourne, Victoria, Australia;
^dAustralian Stem Cell Centre, Monash University, Clayton, Victoria, Australia;
^eDepartment of Pathology, University of Melbourne, Melbourne, Victoria, Australia

Key Words. Hematopoietic stem cell • Mobilization • Hypoxia • Granulocyte colony-stimulating factor • Cyclophosphamide

Correspondence: Jean-Pierre Lévesque, Ph.D., Mater Medical Research Institute, Raymond Terrace, Aubigny Place, South Brisbane, QLD 4101, Australia. Telephone: 61-7-3840-2562; Fax: 61-7-3840-2550; e-mail: jplevesque{at}mmri.mater.org.au

Received October 27, 2006; accepted for publication April 20, 2007.
First published online in STEM CELLS EXPRESS   May 3, 2007.



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-1 (HIF-1) 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-1 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 O₂, 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.

Disclosure of potential conflicts of interest is found at the end of this article.

This article has been cited by other articles:

				K. A. Purpura, S. H.L. George, S. M. Dang, K. Choi, A. Nagy, and P. W. Zandstra Soluble Flt-1 Regulates Flk-1 Activation to Control Hematopoietic and Endothelial Development in an Oxygen-Responsive Manner Stem Cells, November 1, 2008; 26(11): 2832 - 2842. [Abstract] [Full Text] [PDF]

				B. Das, R. Tsuchida, D. Malkin, G. Koren, S. Baruchel, and H. Yeger Hypoxia Enhances Tumor Stemness by Increasing the Invasive and Tumorigenic Side Population Fraction Stem Cells, July 1, 2008; 26(7): 1818 - 1830. [Abstract] [Full Text] [PDF]

				K. L. Congdon, C. Voermans, E. C. Ferguson, L. N. DiMascio, M. Uqoezwa, C. Zhao, and T. Reya Activation of Wnt Signaling in Hematopoietic Regeneration Stem Cells, May 1, 2008; 26(5): 1202 - 1210. [Abstract] [Full Text] [PDF]