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.

Abstract

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

Substances

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