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TISSUE-SPECIFIC STEM CELLS

Tumor Necrosis Factor- Modulates Survival, Proliferation, and Neuronal Differentiation in Neonatal Subventricular Zone Cell Cultures

Neuroprotection and Neurogenesis in Brain Repair Group, Center for Neuroscience and Cell Biology, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

Key Words. Tumor necrosis factor- • Neuronal differentiation • Subventricular zone • Calcium imaging • Histamine • Neurogenesis

Correspondence: Correspondence: João O. Malva, Ph.D., Center for Neuroscience and Cell Biology, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal. Telephone: 351-239-112254; Fax: 351-239-822776; e-mail: jomalva{at}fmed.uc.pt

Received on October 30, 2007; accepted for publication on June 8, 2008.

First published online in STEM CELLS EXPRESS  June 26, 2008.

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.

Disclosure of potential conflicts of interest is found at the end of this article.