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Title: Tumor necrosis factor-alpha modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures
Authors: Bernardino, Liliana 
Agasse, Fabienne 
Silva, Bruno 
Ferreira, Raquel 
Grade, Sofia 
Malva, João O. 
Keywords: Tumor necrosis factor-a; Neuronal differentiation; Subventricular zone; Calcium imaging; Histamine; Neurogenesis
Issue Date: 2008
Publisher: AlphaMed Press
Citation: Stem Cells. 26:9 (2008) 2361-2371
Abstract: Tumor necrosis factor (TNF)- has been reported to modulate brain injury, but remarkably, little is known about its effects on neurogenesis. We report that TNF- strongly influences survival, proliferation, and neuronal differentiation in cultured subventricular zone (SVZ) neural stem/progenitor cells derived from the neonatal P1-3 C57BL/6 mice. By using single-cell calcium imaging, we developed a method, based on cellular response to KCl and/or histamine, that allows the functional evaluation of neuronal differentiation. Exposure of SVZ cultures to 1 and 10 ng/ml mouse or 1 ng/ml human recombinant TNF- resulted in increased differentiation of cells displaying a neuronal-like profile of [Ca2+]i responses, compared with the predominant profile of immature cells observed in control, nontreated cultures. Moreover, by using neutralizing antibodies for each TNF- receptor, we found that the proneurogenic effect of 1 ng/ml TNF- is mediated via tumor necrosis factor receptor 1 activation. Accordingly, the percentage of neuronal nuclear protein-positive neurons was increased following exposure to mouse TNF-. Interestingly, exposure of SVZ cultures to 1 ng/ml TNF- induced cell proliferation, whereas 10 and 100 ng/ml TNF- induced apoptotic cell death. Moreover, we found that exposure of SVZ cells to TNF- for 15 minutes or 6 hours caused an increase in the phospho-stress-activated protein kinase/c-Jun N-terminal kinase immunoreactivity initially in the nucleus and then in growing axons, colocalizing with tau, consistent with axonogenesis. Taken together, these results show that TNF- induces neurogenesis in neonatal SVZ cell cultures of mice. TNF-, a proinflammatory cytokine and a proneurogenic factor, may play a central role in promoting neurogenesis and brain repair in response to brain injury and infection
ISSN: 1066-5099
DOI: 10.1634/stemcells.2007-0914
Rights: openAccess
Appears in Collections:FMUC Medicina - Artigos em Revistas Internacionais

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