Endogenous IGF-1 regulates the neuronal differentiation of adult stem cells

Abstract

Stem cells from the adult forebrain of mice were stimulated to form clones in vitro using fibroblast growth factor-2 (FGF-2). At concentrations above 10 ng/ml of FGF-2, very few clones gave rise to neurons; however, if FGF-2 was removed after 5 days, 20-30% of clones subsequently gave rise to neurons. The number of neuron-containing clones and the number of neurons per clone was significantly enhanced, if insulin-like growth factor (IGF)-1 or heparin were added subsequent to FGF-2 removal. The spontaneous production of neurons after FGF-2 removal was shown to be due to endogenous IGF-1, since antibodies to IGF-1 and an IGF-1 binding protein totally inhibited neuronal production. Similarly, these reagents also abrogated the neuron-promoting effects of heparin. Thus, it appears that endogenous IGF-1 may be a major regulator of stem cell differentiation into neurons. Furthermore, it was found that high levels of IGF-1 or insulin promoted the maturation and affected the neurotransmitter phenotype of the neurons generated.

Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma

“…Both neural stem cells and stem-like cells from brain tumors maintained as neurospheres under the influence of EGF are self-renewing and maintain the potential to differentiate along either neuronal or glial lineages (2, 3, 9, 28). Although no data exist to document the effects of IGF2 on adult neural stem cells, IGF2 has been shown to induce proliferation of cerebellar neuron precursors (29) and IGF2 is implicated as a key factor in supporting expansion of hematopoetic stem cells ex vivo (30). In the current study, we show that IGF2 can support the growth of neurospheres derived from GBMs to the same extent as EGF and that this IGF2-induced effect is mediated, at least in part, through IGF1R.…”

Neuroprotective effects of the Alzheimer's disease-related gene seladin-1

“…The exposure to IGF1 (1-100 nM) stimulated cell growth, reduced apoptosis and increased the release of IGFBP2, whereas it decreased the amount of IGFBP4. It is known that IGFBP2 may facilitate the binding of IGF1 to its receptor (Brooker et al 2000), whereas IGFBP4 is generally considered as a potent inhibitor of the biological effects of IGF1 (Mazerbourg et al 2004). Conversely, intermittent (20 mM or 10 mM, alternatively), but not constant (20 mM), high glucose concentrations significantly reduced FNC cell growth, increased apoptosis and disrupted the IGF system, as demonstrated by the marked reduction of IGF1 and IGFBP2 release.…”

Insulin-Like Growth Factor-I Accelerates the Cell Cycle by Decreasing G1Phase Length and Increases Cell Cycle Reentry in the Embryonic Cerebral Cortex

“…F. Anderson et al, 2002). IGF-I and its cell surface receptor, IGF1R (the type 1 IGF receptor), are expressed throughout the brain during embryonic development (Bondy et al, 1990(Bondy et al, , 1992Ayer-Le Lievre et al, 1991;Bach et al, 1991;Brooker et al, 2000). The capacity of IGF-I to promote neuron progenitor proliferation has been documented in vitro (DiCicco-Bloom and Black, 1988;Torres-Aleman et al, 1990;Drago et al, 1991;Werther et al, 1993;Zackenfels et al, 1995;Arsenijevic et al, 2001) and in vivo Aberg et al, 2000;O'Kusky et al, 2000;Popken et al, 2004), but the influence of IGF-I on cell cycle kinetics in the embryonic brain has not been studied.…”