Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels

Stem Cells. 2007 Sep;25(9):2291-301. doi: 10.1634/stemcells.2006-0609. Epub 2007 Jun 7.


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 1alpha 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 alpha) 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Central Nervous System / cytology*
  • Central Nervous System / drug effects*
  • Central Nervous System / embryology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / drug effects
  • Nuclear Proteins / metabolism
  • Oxygen / pharmacology*
  • Stem Cells / cytology*
  • Stem Cells / drug effects*
  • Tumor Suppressor Protein p53 / metabolism


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • nucleophosmin
  • Oxygen