期刊
STEM CELLS
卷 25, 期 9, 页码 2291-2301出版社
WILEY
DOI: 10.1634/stemcells.2006-0609
关键词
neural stem cells; oxygen; hypoxia; multipotent; expansion; oligodendrocyte
资金
- Intramural NIH HHS Funding Source: Medline
- NICHD NIH HHS [P30HD40677] Funding Source: Medline
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [P30HD040677] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [Z01NS002981, Z01NS002881] Funding Source: NIH RePORTER
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 la 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(lo)CD24(lo) multipotent precursors, a substantial loss of CD133(hi)CD24(lo) multipotent precursors, and a failure of remaining CD133(hi)CD24(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 a) 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.
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