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Severe Hypoxia: Consequences to Neural Stem Cells and Neurons.

ABSTRACT: BACKGROUND:Multiple neurological diseases result from a pathological hypoxia in the brain, resulting in various motor, sensory or cognitive sequelae. Understanding the response of neural stem cells (NSCs) and differentiated neurons to hypoxia will help better treat such diseases. METHODS:We exposed mouse embryonic primary neurons (PN) and neural stem cells to 1% O2 in vitro. RESULTS:Both cell types survived and retained their immunocyto-chemical markers, and neurons showed no obvious morphological changes. Microarray analysis showed that the number of genes with significantly altered expression levels was almost five-fold higher in NSCs compared to PN. NSCs displayed a clear block in G1/S phase of the cell cycle and a number of down-regulated cytokine genes. Various growth factors (e.g. neural growth factor, prolactin), involved in survival and proliferation, genes of the Notch pathway, and genes involved in glial differentiation, and cell-matrix adhesion were up-regulated. PN displayed a down-regulation of a number of genes involved in neuron-specific functions, in particular, transmitter-related (e.g. synaptic transmission, neurotransmitter transport and release, learning, adult behavior). CONCLUSIONS:We conclude that hypoxia 1-down-regulates genes involved in multiple neuronal functions which can negatively impact learning and memory; 2-induces a cell cycle block in NSCs; 3-can precondition NSC towards a particular differentiation potential while maintaining them fully undifferentiated.

SUBMITTER: Felfly H

PROVIDER: S-EPMC3858017 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Severe Hypoxia: Consequences to Neural Stem Cells and Neurons.

Felfly Hady H Zambon Alexander C AC Xue Jin J Muotri Alysson A Zhou Dan D Snyder Evan Y EY Haddad Gabriel G GG

Journal of neurology research 20110101 5

<h4>Background</h4>Multiple neurological diseases result from a pathological hypoxia in the brain, resulting in various motor, sensory or cognitive sequelae. Understanding the response of neural stem cells (NSCs) and differentiated neurons to hypoxia will help better treat such diseases.<h4>Methods</h4>We exposed mouse embryonic primary neurons (PN) and neural stem cells to 1% O<sub>2</sub> in <i>vitro</i>.<h4>Results</h4>Both cell types survived and retained their immunocyto-chemical markers, a ...[more]

PMID: 24348887

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Project description:BackgroundNeural stem cells (NSCs) represent an optimal tool for studies and therapy of neurodegenerative diseases. We recently established a v-myc immortalized human NSC (IhNSC) line, which retains stem properties comparable to parental cells. Oxygen concentration is one of the most crucial environmental conditions for cell proliferation and differentiation both in vitro and in vivo. In the central nervous system, physiological concentrations of oxygen range from 0.55 to 8% oxygen. In particular, in the in the subventricular zone niche area, it's estimated to be 2.5 to 3%.Methodology/principal findingsWe investigated in vitro the effects of 1, 2.5, 5, and 20% oxygen concentrations on IhNSCs both during proliferation and differentiation. The highest proliferation rate, evaluated through neurosphere formation assay, was obtained at 2.5 and 5% oxygen, while 1% oxygen was most noxious for cell survival. The differentiation assays showed that the percentages of beta-tubIII+ or MAP2+ neuronal cells and of GalC+ oligodendrocytes were significantly higher at 2.5% compared with 1, 5, or 20% oxygen at 17 days in vitro. Mild hypoxia (2.5 to 5% oxygen) promoted differentiation into neuro-oligodendroglial progenitors as revealed by the higher percentage of MAP2+/Ki67+ and GalC+/Ki67+ residual proliferating progenitors, and enhanced the yield of GABAergic and slightly of glutamatergic neurons compared to 1% and 20% oxygen where a significant percentage of GFAP+/nestin+ cells were still present at 17 days of differentiation.Conclusions/significanceThese findings raise the possibility that reduced oxygen levels occurring in neuronal disorders like cerebral ischemia transiently lead to NSC remaining in a state of quiescence. Conversely, mild hypoxia favors NSC proliferation and neuronal and oligodendroglial differentiation, thus providing an important advance and a useful tool for NSC-mediated therapy of ischemic stroke and neurodegenerative diseases like Parkinson's disease, multiple sclerosis, and Alzheimer's disease.

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Severe Hypoxia: Consequences to Neural Stem Cells and Neurons.

Publications

Severe Hypoxia: Consequences to Neural Stem Cells and Neurons.

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