Open AccessTumor Necrosis Factor‐α Modulates Survival, Proliferation, and Neuronal Differentiation in Neonatal Subventricular Zone Cell Cultures
Author(s) -
Bernardino Liliana,
Agasse Fabienne,
Silva Bruno,
Ferreira Raquel,
Grade Sofia,
Malva João O.
Publication year - 2008
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1634/stemcells.2007-0914
Subject(s) - subventricular zone , biology , neurogenesis , tumor necrosis factor alpha , microbiology and biotechnology , neural stem cell , progenitor cell , necrosis , stem cell , endocrinology , genetics
Tumor necrosis factor (TNF)‐α has been reported to modulate brain injury, but remarkably, little is known about its effects on neurogenesis. We report that TNF‐α 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‐α resulted in increased differentiation of cells displaying a neuronal‐like profile of [Ca 2+ ] i responses, compared with the predominant profile of immature cells observed in control, nontreated cultures. Moreover, by using neutralizing antibodies for each TNF‐α receptor, we found that the proneurogenic effect of 1 ng/ml TNF‐α 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‐α. Interestingly, exposure of SVZ cultures to 1 ng/ml TNF‐α induced cell proliferation, whereas 10 and 100 ng/ml TNF‐α induced apoptotic cell death. Moreover, we found that exposure of SVZ cells to TNF‐α 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‐α induces neurogenesis in neonatal SVZ cell cultures of mice. TNF‐α, 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.