Evidence for a major role of endogenous fibroblast growth factor-2 in apoptotic cortex-induced subventricular zone cell proliferation

In the adult mammalian brain, neural stem cells persist in the subventricular zone (SVZ) of lateral ventricles. It is well established that cortical damage leads to SVZ cell proliferation and neuronal differentiation. We have previously demonstrated in rat that, when treated with the apoptosis-inducing agent staurosporine, cortex explants release heat-labile factors that promote SVZ cell culture proliferation. In the present report, we investigated in vitro mechanisms involved in cortex injury-triggered neurogenesis in the rat. We demonstrated, using immunoblotting analysis and fibroblast growth factor (FGF)-2 enzyme-linked sandwich immunosorbent assay, that treatment of cortex explants with apoptosis-inducing agents increases the release of FGF-2. We next determined the effects of apoptotic cortex-released factors in regulating SVZ cell proliferation and neuronal differentiation by using bromodeoxyuridine incorporation and microtubule- associated protein 2 immunostaining assays, respectively. We found that conditioned media derived from staurosporine-treated cortex explants enhanced SVZ cell culture proliferation and differentiation by over 50 and 80%, respectively. Finally, we showed that immunodepletion of FGF-2 or pharmacological blockade of FGF-2 receptor by SU5402 completely abolished staurosporine-treated cortex mitogenic activity on SVZ cultures but did not alter its activity on neuronal cell differentiation. Altogether, the present report establishes that the release of endogenous FGF-2 by apoptotic cortex explants plays a major role in the induction of SVZ cell proliferation but not neuronal differentiation, which probably depends on the release of other as yet unidentified cortical factors.