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.
Highlights
Many studies over the past decade have touted the regenerative potential of the endogenous neural precursors (NPs) of the subventricular zone (SVZ) following injury
Considering the results of the studies reviewed in the Introduction together with our data, we hypothesized that insulin-like growth factor (IGF)-1R is necessary for the expansion of NPs following brain injury in the presence of epidermal growth factor (EGF)
We performed experiments to evaluate the necessity of IGF-1R signaling by lowering the insulin concentration in the media, to levels that only stimulate insulin receptor (IR), from 25 μg/ml “high” to 25 ng/ml “low” in NPs when exposed to EGF, FGF-2, or both
Summary
Many studies over the past decade have touted the regenerative potential of the endogenous neural precursors (NPs) of the subventricular zone (SVZ) following injury. We used flow cytometry on SVZ cells isolated acutely after neonatal hypoxia–ischemia (H–I) and showed that epidermal growth factor receptor (EGFR) expression increased significantly on primitive NPs of the SVZ during recovery from neonatal H– I. The critical importance of IGFs for neural development was shown in studies that produced genetically engineered mice with disrupted IGF-I gene expression. These gene targeted mice showed profound in utero and postnatal growth retardation [2]. IGF-II knockouts showed similar growth retardation with onset earlier during gestation and, like the IGF-1 deficient mice, showed a 40% reduction in body mass at birth [3]. Homozygous IGF-1R null mice have more profound developmental deficits at the end of gestation, and they do not survive beyond a few hours after birth [2]
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