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The Journal of Neuroscience, October 1, 2000, 20(19):7377-7383
Enhanced Proliferation, Survival, and Dopaminergic Differentiation of CNS Precursors in Lowered Oxygen
Lorenz Studer1, 3, Marie Csete2, 4, Sang-Hun Lee1, 5, Nadine Kabbani1, Jean Walikonis2, Barbara Wold2, and Ron McKay1 1 Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, 2 Biology Division, California Institute of Technology, Pasadena, California 92215, 3 Laboratory of Stem Cell and Tumor Biology, Neurosurgery and Cellular Biochemistry and Biophysics, Sloan Kettering, New York, New York 10021, 4 Departments of Anesthesiology, and Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-0615, and 5 College of Medicine, Hanyang University, Seoul, 133-791, Korea
Standard cell culture systems impose environmental oxygen (O2) levels of 20%, whereas actual tissue O2 levels in both developing and adult brain are an order of magnitude lower. To address whether proliferation and differentiation of CNS precursors in vitro are influenced by the O2 environment, we analyzed embryonic day 12 rat mesencephalic precursor cells in traditional cultures with 20% O2 and in lowered O2 (3 ± 2%). Proliferation was promoted and apoptosis was reduced when cells were grown in lowered O2, yielding greater numbers of precursors. The differentiation of precursor cells into neurons with specific neurotransmitter phenotypes was also significantly altered. The percentage of neurons of dopaminergic phenotype increased to 56% in lowered O2 compared with 18% in 20% O2. Together, the increases in total cell number and percentage of dopaminergic neurons resulted in a ninefold net increase in dopamine neuron yield. Differential gene expression analysis revealed more abundant messages for FGF8, engrailed-1, and erythropoietin in lowered O2. Erythropoietin supplementation of 20% O2 cultures partially mimicked increased dopaminergic differentiation characteristic of CNS precursors cultured in lowered O2. These data demonstrate increased proliferation, reduced cell death, and enhanced dopamine neuron generation in lowered O2, making this method an important advance in the ex vivo generation of specific neurons for brain repair.
Key words: CNS precursors; CNS stem cells; dopaminergic neurons; erythropoietin; oxygen; Parkinson's disease
Copyright © 2000 Society for Neuroscience 0270-6474/00/20197377-07$05.00/0
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