Endogenous Hepatocyte Growth Factor is a niche signal for neural stem for neural stem cell proliferation and self-renewal
Résumé
The subventricular zone (SVZ) of the forebrain is a major source of neural stem cells (NSCs) in the adult brain. Although many studies have identified exogenous mechanisms of NSC control, the endogenous mechanisms regulating the neurogenic activity of NSC have only poorly been explored. 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. Hepatocyte Growth Factor (HGF) was responsible for LCM mitogenic activity and addition of exogenous HGF stimulated SVZ cell proliferation and expansion of cells endowed with self-renewal properties both in vitro and in vivo. The HGF receptor, c-met, was detected in SVZ cells and was found to be linked to the MAP-kinase signalling pathway. Furthemore, HGF was immunodetected in SVZ cells and conditioned media derived from SVZ cells were found to contain biologically active HGF. 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 endogenous HGF as a major regulator of NSCs activity within the neurogenic niche