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.