Insulin-like growth factor-I is necessary for neural stem cell proliferation and demonstrates distinct actions of epidermal growth factor and fibroblast growth factor-2
Neural stem cells (NSCs), when stimulated with epidermal growth factor (EGF) or fibroblast growth factor-2 (FGF-2), have the capacity to renew, expand, and produce precursors for neurons, astrocytes, and oligodendrocytes. We postulated that the early appearance of insulin-like growth factor (IGF-I) receptors during mouse striatum development implies a role in NSC regulation. Thus, we tested in vitro the action of IGF-I on the proliferation of striatal NSCs. In the absence of IGF-I, neither EGF nor FGF-2 was able to induce the proliferation of E14 mouse striatal cells. However, addition of IGF-I generated large proliferative clusters, termed spheres, in a dose-dependent manner. The newly generated spheres were multipotent, and clonal analysis revealed that EGF or FGF-2, in the presence of IGF-I, acted directly on NSCs. The actions of IGF-I suggest distinct modes of action of EGF or FGF-2 on NSCs. First, continuous versus delayed administration of these neurotrophic factors showed that neither IGF-I nor EGF had an effect on NSC survival, whereas FGF-2 promoted the survival or maintenance of the stem cell state of 50% of NSCs for 6 d. Second, short-term exposure to IGF-I induced the proliferation of NSCs in the presence of EGF, but not of FGF-2, through an autocrine secretion of IGF-I. These findings suggest that IGF-I is a key factor in the regulation of NSC activation and that EGF and FGF-2 control striatal NSC proliferation, in part, through distinct intracellular mechanisms.
Keywords: Animals ; Autocrine Communication/drug effects/physiology ; Cell Count ; Cell Division/drug effects ; Cell Survival/drug effects ; Cells ; Cultured ; Corpus Striatum ; Dose-Response Relationship ; Drug ; Epidermal Growth Factor/ pharmacology ; Fibroblast Growth Factor 2/ pharmacology ; Insulin-Like Growth Factor I/ pharmacology ; Mice ; Neurons/cytology/ drug effects/metabolism ; Spheroids ; Cellular/cytology/drug effects ; Stem Cells/cytology/ drug effects/metabolism
Division of Surgical Research and Gene Therapy Center, Pavillon 4 Centre Hospitalier Universitaire Vaudois, 1004 Lausanne, Switzerland. Yvan.Arsenijevic@chuv.hospvd.ch
Record created on 2007-03-09, modified on 2016-08-08