Transcriptional profiling of human cord blood CD133⁺ and cultured bone marrow mesenchymal stem cells in response to hypoxia

¹ Stem Cell Research Laboratory, National Blood Service, Oxford Centre, The John Radcliffe Hospital, Oxford, United Kingdom
² MRC-Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
³ Stem Cell Research Laboratory, National Blood Service, Oxford Centre, The John Radcliffe Hospital, Oxford, United Kingdom; Nuffield Department of Clinical and Laboratory Sciences, University of Oxford, Oxford, United Kingdom
⁴ Cancer Research UK, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Oxford, United Kingdom

^* To whom correspondence should be addressed. E-mail: enca.martin-rendon{at}nbs.nhs.uk.

	Abstract

Umbilical cord blood (UCB) and bone marrow (BM)-derived stem and progenitor cells possess two characteristics required for successful tissue regeneration, which are 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, proliferation and differentiation potential of UCB CD133⁺ cells and BM mesenchymal cells (BMMC) exposed to normoxia and hypoxia were analysed and compared. Both progenitor cell populations responded to hypoxic stimuli by stabilising the HIF1- 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 BMMC was enhanced by hypoxia, whilst 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 RT-PCR. These results therefore provide a global view of the signalling and regulatory network that controls oxygen sensing in human adult stem/progenitor cells derived from haematopoietic tissues.

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