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STEM CELL GENETICS AND GENOMICS |
aStem Cell Research Laboratory, National Blood Service, Oxford Centre, The John Radcliffe Hospital, Oxford, United Kingdom;
bMRC-Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;
cNuffield Department of Clinical and Laboratory Sciences, University of Oxford, Oxford, United Kingdom;
dCancer Research UK, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Oxford, United Kingdom
Key Words. Human stem cells • CD133+ cells • Mesenchymal stem cells • Hypoxia • Transcriptome • Proliferation • Differentiation Bone marrow • Cord blood
Correspondence: Enca Martin-Rendon, Ph.D., Stem Cell Research Laboratory, National Blood Service, John Radcliffe Hospital, Headington, OX3 9BQ, United Kingdom. Telephone: +44 1865-447934; Fax: +44 1865-764376; e-mail: enca.martin-rendon{at}nbs.nhs.uk
Received June 29, 2006;
accepted for publication December 13, 2006.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS December 21, 2006.
Umbilical cord blood (UCB) and bone marrow (BM)-derived stem and progenitor cells possess two characteristics required for successful tissue regeneration: extensive proliferative capacity and the ability to differentiate into multiple cell lineages. Within the normal BM and in pathological conditions, areas of hypoxia may have a role in maintaining stem cell fate or determining the fine equilibrium between their proliferation and differentiation. In this study, the transcriptional profiles and proliferation and differentiation potential of UCB CD133+ cells and BM mesenchymal cells (BMMC) exposed to normoxia and hypoxia were analyzed and compared. Both progenitor cell populations responded to hypoxic stimuli by stabilizing the hypoxia inducible factor (HIF)-1
protein. Short exposures to hypoxia increased the clonogenic myeloid capacity of UCB CD133+ cells and promoted a significant increase in BMMC number. The differentiation potential of UCB CD133+ clonogenic myeloid cells was unaltered by short exposures to hypoxia. In contrast, the chondrogenic differentiation potential of BMMCs was enhanced by hypoxia, whereas adipogenesis and osteogenesis were unaltered. When their transcriptional profiles were compared, 183 genes in UCB CD133+ cells and 45 genes in BMMC were differentially regulated by hypoxia. These genes included known hypoxia-responsive targets such as BNIP3, PGK1, ENO2, and VEGFA, and other genes not previously described to be regulated by hypoxia. Several of these genes, namely CDTSPL, CCL20, LSP1, NEDD9, TMEM45A, EDG-1, and EPHA3 were confirmed to be regulated by hypoxia using quantitative reverse transcriptase polymerase chain reaction. These results, therefore, provide a global view of the signaling and regulatory network that controls oxygen sensing in human adult stem/progenitor cells derived from hematopoietic tissues.
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