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.
Arsenijevic
Y
Y
Division of Surgical Research and Gene Therapy Center, Pavillon 4 Centre Hospitalier Universitaire Vaudois, 1004 Lausanne, Switzerland. Yvan.Arsenijevic@chuv.hospvd.ch
Weiss
S
S
Schneider
B
B
Aebischer
P
P
D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I