Abstract
Strategies to enhance the capacity of grafted stem/progenitors cells to generate multipotential, proliferative and migrating pools of cells in the postnatal brain could be crucial for structural repair after brain damage. We investigated whether the over-expression of basic fibroblast growth factor 2 (FGF-2) in neural progenitor cells (NPCs) could provide a robust source of migrating NPCs for tissue repair in the rat cerebral cortex. Using live imaging we provide direct evidence that FGF-2 over-expression significantly enhances the migratory capacity of grafted NPCs in complex 3D structures, such as cortical slices. Furthermore, we show that the migratory as well as proliferative properties of FGF-2 over-expressing NPCs are maintained after in vivo transplantation. Importantly, after transplantation into a neonatal ischaemic cortex, FGF-2 over-expressing NPCs efficiently invade the injured cortex and generate an increased pool of immature neurons available for brain repair. Differentiation of progenitor cells into immature neurons was correlated with a gradual down-regulation of the FGF-2 transgene. These results reveal an important role for FGF-2 in regulating NPCs functions when interacting with the host tissue and offer a potential strategy to generate a robust source of migrating and immature progenitors for repairing a neonatal ischaemic cortex.
Highlights
Expression of FGF-2 in neural progenitorsBrain (2007), 130, 2962^2976 2963 in regenerating new hippocampal neurons after global ischaemia (Nakatomi et al, 2002)
To study the effects of FGF-2 over-expression in multipotential NPCs, subventricular zone (SVZ) cells were isolated from newborn rats and expanded as described previously (Zhang et al, 2003)
Cultures were transduced after 3 days in vitro (DIV3) with either the control green fluorescent protein (GFP) lentiviral vector or the FGF-2-GFP lentiviral vector
Summary
Expression of FGF-2 in neural progenitorsBrain (2007), 130, 2962^2976 2963 in regenerating new hippocampal neurons after global ischaemia (Nakatomi et al, 2002). Among the multiple factors limiting the efficiency of NPC transplantation in the postnatal cortex is the fact that grafted NPCs rapidly lose their immature, proliferative and migratory properties. It would be of considerable interest to supply a source population of multipotential, proliferative and migrating NPCs competent to respond to chemoattractant cues secreted by the site of injury. Support for this hypothesis derives from in vitro work showing that FGF-2-stimulated NPCs can respond to a chemoattractant cue such as vascular endothelial growth factor (Zhang et al, 2003). We tested the hypothesis that over-expression of FGF-2 in transplanted NPCs may provide robust sources of migrating NPCs for tissue repair after brain damage
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