title: Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels.
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.
authors.affiliation: Center for Neuroscience Research, Children's National Medical Center, Washington, DC, USA.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Chen
authors.forename: Francesca
authors.initials: F
authors.lastname: Pistollato
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hoeppner
authors.forename: Hsiao-Tzu
authors.initials: HT
authors.lastname: Ni
authors.forename: Ronald D G
authors.initials: RD
authors.lastname: McKay
authors.forename: David M
authors.initials: DM
authors.lastname: Panchision
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology* / Q000187:drug effects* / Q000196:embryology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D010100:Oxygen / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; D010100:Oxygen