Effects Of Fgfs In Vivo And In Vitro

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During recent years several studies have shown that FGFs exert multiple trophic actions on cells of the nervous system. In this chapter, however, the focus will be exclusively on those effects of FGFs which might be relevant for the development of therapeutic strategies of nerve injury or disorder. The observation that FGFs display neurotrophic potential12-14 and are mitogenic for neuronal and glial precursor cells has raised high hopes to rescue neurons from cell death after injury and during disease, or to replace them by differentiating neuronal progenitors, thereby restoring brain function.110 Several studies have shown that FGF-2 together with epidermal growth factor (EGF) is a key molecule regulating the differentiation of neural precursors in vitro. FGF-2 stimulates both the proliferation and survival of embryonic cells from the striatum,111 and in addition, increases proliferation in cultures of rat embryonic hemispheres, hippocampus, and spinal cord.112-116 The majority of the generated cells display a neuronal phenotype. Comparison between the effects of EGF and FGF-2 on developing CNS precursors expanded by each factor revealed the ability of FGF-2 to stimulate proliferation of a multipotential precursor, giving rise to neurons and astrocytes as well as a committed glial precursor, whereas EGF only stimulates the glial precursor.117 A recent report suggests that FGF-2 could also promote division of cortical glutaminergic precursor cells, but not of GABAergic precursors, which would allow independent regulation of these two major classes of cortical cells.118 Division and delay of differentiation of dopamine precursor cells is also influenced by FGF-2.119

The olfactory bulb and the hippocampal dentate gyrus are the only structures that display generation of neurons well into adult life. It is, however, possible to isolate neural precursor cells from the adult brain using in vitro culture systems and the appropriate factors.120-123 FGF-2 stimulates proliferation of precursor cells from the adult mouse brain.124-126 The majority of the progeny of these cells were of an astrocytic phenotype,121 whereas mitogenic action of FGF-2 on precursor cells from the adult hippocampus produced both neurons and astrocytes under the culture conditions used.127

Proliferation and differentiation of glial cells is also influenced by FGF-2. It is a mitogen for cultured oligodendrocytes128 and modulates the platelet-derived, growth factor-driven pathway of oligodendrocyte development.129

It has also been shown that FGF-2 is able to rescue cells from cell death and stimulates transmitter metabolism of dopaminergic neurons,130-133 cholinergic septal neurons,134 and motoneurons.135-140 Although it has been shown that FGF-2 can act directly on neurons141 the neurotrophic effect of FGF-2 is indirect and is most likely mediated by glial cells.131 Nevertheless, FGF-2 has been applied successfully in a variety of different lesion models. Whereas the first of these studies directly applied FGF (injection, gel foams), recent studies have used the transplantation of genetically modified cells for trophic factor supply. It was demonstrated that exogenously applied FGF-2 undergoes receptor-mediated retrograde transport in various CNS neurons.138142 Following fimbria-fornix transection, cholinergic septal neurons are rescued by FGF-2 which was injected or applied in a gel foam.143-146 In combination with the ganglioside GM1, FGF-2 can improve spatial memory deficits after partial fimbria transection.147

Degeneration of the dopaminergic nigrostriatal system, such as the reduction of the striatal dopamine and tyrosine hydroxylase immunoreactivity induced by MPTP, can be opposed by exogenously administered FGF-2.148-150 It was also reported that FGF-2, continuously infused into the lateral ventricle, can rescue hippocampal CA1 neurons from ischemic-induced death.151 In a rat neonatal model of hypoxia ischemia, intraperitoneal administration of FGF-2 exerts dose-dependent neuroprotective effects.152 Grafting of genetically engineered fibroblasts producing FGF-2 into the lesion cavity prevents death of entorhinal layer II glutamatergic neurons following lesion of the perforant pathway in rats.153 After ablation of the somatosensory cortex, implantation of a gelfoam soaked with FGF-2 into the lesion cavity prolongs the lesion-induced increase of the c-Zbs-mRNA expression in nonneuronal cells of the cortex, suggesting that FGF-2 could enhance the contribution of c-ibs to neuronal plasticity.154

Preganglionic sympathetic neurons of the intermediolateral column of the spinal cord (Th7-10) give rise to the peripheral splanchnic nerves that innervate the chromaffin cells of the adrenal medulla. Target ablation by adrenomedullectomy leads to a lesion-induced death of the preganglionic sympathetic neurons, which is prevented by the substitution of the ablated adrenal medulla with FGF-2.155 Since iodinated FGF-2 injected into the adrenal medulla is specifically retrogradely transported by preganglionic sympathetic neurons,29 and FGF-2 is synthesized in the adrenal medulla,60 this rescue effect might be of physiological relevance.

In addition to FGF-2, two other members of the FGF family, FGF-1 and FGF-4, have been shown to display regenerative potential in vivb. FGF-1 was used to partially restore hind limb functions in adult paraplegic rats.156 Transplantation of FGF-4-secreting Schwannoma cells as a bridge graft stimulated axonal regrowth in the mechanically lesioned adult rat nigrostriatal pathway.157

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