Hepatocyte Growth Factor is a niche signal for neural stem cell proliferation
Résumé
The subventricular zone (SVZ) of the forebrain is a major source of neural stem cells (NSCs) in the adult brain. Given their capacity to produce new neurons throughout life, NSC display a potential therapeutical use for the treatment of neuropathological diseases and therefore have been the focus of numerous studies during the past years. Our study aims at identifying endogenous mechanisms regulating the neurogenic activity of NSCs. Based on the shared features of the germinative regions in the organism, we identified that, in vitro, adult rat liver conditioned media (LCM) stimulate SVZ cell proliferation. Immunodepletion experiments indicated that endogenous Hepatocyte Growth Factor (HGF) was responsible for LCM mitogenic effect. Conversely, addition of exogenous HGF stimulated SVZ cell proliferation and expansion of cells endowed with self-renewal properties. Accordingly, the cognate HGF receptor, c-met, was detected in SVZ cells expressing nestine and LeX-SSEA1, two epitopes enriched in SVZ stem-like cells, and was found to be linked to the MAP-kinase signalling pathway. A physiological role for HGF was next determined in the brain. HGF was immunodetected in SVZ cells and conditioned media derived from SVZ cells were found to contain biologically active HGF, as determined by the classical MDCK cells scattering test. Furthermore, within SVZ cell cultures, addition of HGF neutralizing antibodies inhibited mitogenic activity induced by the SVZ conditioned media, thus indicating that endogenous HGF produced by SVZ cells promotes proliferation within the SVZ neurogenic niche. Brain sections immunostaining revealed that both HGF and c-met are expressed in vivo within the SVZ. HGF intracerebroventricular injection promoted SVZ cells proliferation and increased the ability of these cells exposed in vivo to HGF to form neurospheres in vitro whereas intracerebroventricular injection of HGF neutralizing antibodies decreased SVZ cells proliferation. Our study identifies HGF as a major endogenous regulator of NSCs activity within the neurogenic niche. By increasing knowledge of endogenous mechanisms controlling proliferation of SVZ cells, our study will help improve neural stem cell based therapies of brain diseases.