Insulin-Like Growth Factor Receptor Signaling is Necessary for Epidermal Growth Factor Mediated Proliferation of SVZ Neural Precursors in vitro Following Neonatal Hypoxia–Ischemia

Abstract

In this study, we assessed the importance of insulin-like growth factor (IGF) and epidermal growth factor (EGF) receptor co-signaling for rat neural precursor (NP) cell proliferation and self-renewal in the context of a developmental brain injury that is associated with cerebral palsy. Consistent with previous studies, we found that there is an increase in the in vitro growth of subventricular zone NPs isolated acutely after cerebral hypoxia–ischemia; however, when cultured in medium that is insufficient to stimulate the IGF type 1 receptor, neurosphere formation and the proliferative capacity of those NPs was severely curtailed. This reduced growth capacity could not be attributed simply to failure to survive. The growth and self-renewal of the NPs could be restored by addition of both IGF-I and IGF-II. Since the size of the neurosphere is predominantly due to cell proliferation we hypothesized that the IGFs were regulating progression through the cell cycle. Analyses of cell cycle progression revealed that IGF-1R activation together with EGFR co-signaling decreased the percentage of cells in G1 and enhanced cell progression into S and G2. This was accompanied by increases in expression of cyclin D1, phosphorylated histone 3, and phosphorylated Rb. Based on these data, we conclude that coordinate signaling between the EGF receptor and the IGF type 1 receptor is necessary for the normal proliferation of NPs as well as for their reactive expansion after injury. These data indicate that manipulations that maintain or amplify IGF signaling in the brain during recovery from developmental brain injuries will enhance the production of new brain cells to improve neurological function in children who are at risk for developing cerebral palsy.

Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease

“…IGF‐I impacts multiple cellular behaviors, including proliferation, migration, and differentiation [29–32]. Bearing in mind our goal to develop HK532‐IGF‐I into a cellular therapy for use in patients, we next confirmed that that autocrine production of IGF‐I does not adversely impact cell behavior.…”

“…Insulin-like growth factor-I (IGF-I) is an essential trophic factor for neuronal development and normal function [27,28]. Signaling through the IGF-I receptor (IGF-IR) stimulates proliferation and differentiation [29][30][31][32], and exerts neuroprotective effects via activation of two major signaling pathways: the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/ Akt pathway [33,34]. These neuroprotective effects are seen in multiple cell types, including cholinergic and hippocampal neurons [33,[35][36][37].…”

Cyclin-Dependent Kinase 4 Regulates Adult Neural Stem Cell Proliferation and Differentiation in Response to Insulin

“…Differential activation of IRS1‐ versus IRS2‐associated signaling complexes has been observed in other cell types: in fibroblasts, specific activation of IRS2 by IGF‐I through the insulin receptor does not engage MAPK but does trigger the PI3K/AKT pathway to enhance cell viability . Consistent with this notion of specificity, FGF‐2 stimulation of oligodendrocyte progenitors activates the MAPK pathway which promotes cyclin D1 mRNA expression, whereas IGF‐I activation of the PI3K pathway inhibits proteasome degradation of cyclin D1 and enhances nuclear localization of cyclin D1 . Thus, insulin and IGFs may selectively use IRS2 in NSCs to regulate Cdk4 via activation of the Akt pathway.…”

Neural Stem Cells and Nutrients: Poised Between Quiescence and Exhaustion

“…Both IGF-I and insulin (to a lesser extent) induce proliferation of NSCs in adult rat hippocampus and in culture (neurosphere assay [47]), but their effect is dependent on the presence of other growth factors such as epidermal growth factor (EGF) [48]. In particular, IGF-I and EGF cosignaling favors cell proliferation and self-renewal in rat neural precursors [49].…”