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TISSUE-SPECIFIC STEM CELLS

Oxygen Tension Regulates Survival and Fate of Mouse Central Nervous System Precursors at Multiple Levels

^aCenter for Neuroscience Research, Children's National Medical Center, Washington, DC, USA;
^bHemato-Oncology Laboratory, Department of Pediatrics, University of Padua, Padua, Italy;
^cLaboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA;
^dR&D Systems, Inc., Minneapolis, Minnesota, USA

Key Words. Neural stem cells • Oxygen • Hypoxia • Multipotent • Expansion • Oligodendrocyte

Correspondence: David M. Panchision, Ph.D., 5th Floor, Suite 5340, 111 Michigan Avenue NW, Washington, DC 20010, USA. Telephone: 202-884-2269; Fax: 202-884-4988; e-mail: dpanchision{at}cnmcresearch.org

Received September 28, 2006; accepted for publication May 30, 2007.
First published online in STEM CELLS EXPRESS   June 7, 2007.



Despite evidence that oxygen regulates neural precursor fate, the effects of changing oxygen tensions on distinct stages in precursor differentiation are poorly understood. We found that 5% oxygen permitted clonal and long-term expansion of mouse fetal cortical precursors. In contrast, 20% oxygen caused a rapid decrease in hypoxia-inducible factor 1 and nucleophosmin, followed by the induction of p53 and apoptosis of cells. This led to a decrease in overall cell number and particularly a loss of astrocytes and oligodendrocytes. Clonal analysis revealed that apoptosis in 20% oxygen was due to a complete loss of CD133^loCD24^lo multipotent precursors, a substantial loss of CD133^hiCD24^lo multipotent precursors, and a failure of remaining CD133^hiCD24^lo cells to generate glia. In contrast, committed neuronal progenitors were not significantly affected. Switching clones from 5% to 20% oxygen only after mitogen withdrawal led to a decrease in total clone numbers but an even greater decrease in oligodendrocyte-containing clones. During this late exposure to 20% oxygen, bipotent glial (A2B5⁺) and early (platelet-derived growth factor receptor ) oligodendrocyte progenitors appeared and disappeared more quickly, relative to 5% oxygen, and late stage O4⁺ oligodendrocyte progenitors never appeared. These results indicate that multipotent cells and oligodendrocyte progenitors are more susceptible to apoptosis at 20% oxygen than committed neuronal progenitors. This has important implications for optimizing ex vivo production methods for cell replacement therapies.

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

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