Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Microarray analysis of ischemic lesions of WT and TNFRI KO mice

ABSTRACT: TNF/TNFRI signaling has previously been shown to exert neuroprotective effects after brain ischemic injury. However, the detailed pathways involved remain unidentified. This study aims to identify key neuroprotective molecules activated by TNFRI after permanent ischemic injury in mice. Microarray analysis of the ipsilateral hemispheres of WT and TNFRI knockout at early time points (3 and 6 hours) after the middle cerebral artery occlusion mice were chosen to study the CNS response to injury without significant immune infiltration. Using the ATLAS mouse cDNA arrays that include known genes representative of multiple pathways, we identify novel protective pathways triggered by TNFRI signaling after ischemia. Keywords: brain, ischemic lesion, comparison between WT and TNFRI knockout mice, cDNA array, two different time points (3 and 6 h) RNA was extracted from WT (n=2) and TNFRI KO (n=2) mice at each time point studied (3 and 6 h after ischemia). For each individual sample two hybridisations were performed.

ORGANISM(S): Mus musculus

SUBMITTER: Era Taoufik

PROVIDER: E-GEOD-8886 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury.

Taoufik Era E Petit Edwige E Divoux Didier D Tseveleki Vivian V Mengozzi Manuela M Roberts Michael L ML Valable Samuel S Ghezzi Pietro P Quackenbush John J Brines Michael M Cerami Anthony A Probert Lesley L

Proceedings of the National Academy of Sciences of the United States of America 20080414 16

CNS neurons use robust cytoprotective mechanisms to ensure survival and functioning under conditions of injury. These involve pathways induced by endogenous neuroprotective cytokines such as erythropoietin (EPO). Recently, in contrast to its well known deleterious roles, TNF has also been shown to exhibit neuroprotective properties. In the present study, we investigated the molecular mechanisms by which TNF receptor (TNFR)I mediates neuroprotection by comparing the gene expression profiles of le ...[more]

PMID: 18413601

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Project description:Primary cortical neurons were isolated from E15 mice and after 5 days in vitro were untreated or treated for 24 h with mesenchymal stem cell conditioned medium and then untreated or treated for a further 24 h with NMDA. Neuron gene expression was profiled and compared between the four different conditions (neurons, neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA) to investigate the molecular mechanisms of MSC neuroprotection. Mesenchymal stem cells (MSC) promote functional recovery in experimental models of central nervous system (CNS) pathology and are currently being tested in clinical trials for stroke, multiple sclerosis and CNS injury. Their beneficial effects are attributed to activation of endogenous CNS repair processes and immune regulation but their mechanisms of action are poorly understood. Here we investigated the neuroprotective effects of MSC in simplified MSC-neuron co-culture systems and in mice using models of glutamate excitotoxicity. MSC protected primary cortical neurons against glutamate (NMDA) receptor-induced death and conditioned medium from MSC (MSC cm), but not control NIH3T3 cells, was sufficient for this effect. MSC cm neuroprotection in mouse cortical neurons was reduced by neutralizing antibodies to bFGF and associated with altered gene expression in neurons towards an immature phenotype as well as reduced neuronal Grin1, Grin2a and Grin2b mRNA levels in response to NMDA stimulation. Further, MSC cm neuroprotection in rat retinal ganglion cells was associated with absence of glutamate-induced calcium influx. Adoptive transfer of EGFP+MSC in a mouse kainic acid seizure model reduced CA3 neuron damage and hippocampal astrocytosis and resulted in the increased expression of neuronal genes that are upregulated by MSC cm, Bmi1, Ddx4, Ezh1, in the hippocampus. These results show that MSC mediate direct neuroprotection against glutamate excitotoxicity by secreting bFGF, reducing glutamate receptor expression and function and altering neuron gene expression towards an immature pattern, and provide evidence for a link between the therapeutic effects of MSC and the activation of endogenous repair processes following CNS injury. In vitro cultures primary cortical neurons from mice were protected from glutamate excitotoxicity when pre-treated with MSC cm. Global gene expression changes induced in neurons before and after treatment with MSC cm and/or NMDA were investigated using a cDNA spotted macroarray filter. Four samples were analysed in duplicate: neurons alone (untreated), neurons+MSC cm, neurons+NMDA, neurons+MSC cm+NMDA.

Dataset Information

Microarray analysis of ischemic lesions of WT and TNFRI KO mice

Publications

TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury.

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