Epidermal Growth Factor and Fibroblast Growth Factor-2 Have Different Effects on Neural Progenitors in the Adult Rat Brain

Abstract

Neurons and glia are generated throughout adulthood from proliferating cells in two regions of the rat brain, the subventricular zone (SVZ) and the hippocampus. This study shows that exogenous basic fibroblast growth factor (FGF-2) and epidermal growth factor (EGF) have differential and site-specific effects on progenitor cells in vivo. Both growth factors expanded the SVZ progenitor population after 2 weeks of intracerebroventricular administration, but only FGF-2 induced an increase in the number of newborn cells, most prominently neurons, in the olfactory bulb, the normal destination for neuronal progenitors migrating from the SVZ. EGF, on the other hand, reduced the total number of newborn neurons reaching the olfactory bulb and substantially enhanced the generation of astrocytes in the olfactory bulb. Moreover, EGF increased the number of newborn cells in the striatum either by migration of SVZ cells or by stimulation of local progenitor cells. No evidence of neuronal differentiation of newborn striatal cells was found by threedimensional confocal analysis, although many of these newborn cells were associated closely with striatal neurons. The proliferation of hippocampal progenitors was not affected by either growth factor. However, EGF increased the number of newborn glia and reduced the number of newborn neurons, similar to the effects seen in the olfactory bulb. These findings may be useful for elucidating the in vivo role of growth factors in neurogenesis in the adult CNS and may aid development of neuronal replacement strategies after brain damage.

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

“…Infusion of FGF2 into the lateral ventricle resulted in enhanced neurogenesis within the SVZ and a subsequent increase in the number of new neurons in the olfactory bulb, whereas similar infusion of EGF resulted in a decrease of new neurons in the olfactory bulb. The latter was associated with a significant increase of astrocytes in the neighboring striatum [84,92]. These observations are in contrast with a previous report demonstrating an increase in neural recruitment to the olfactory bulb and a recruitment of new neurons to the striata following intraventricular infusion of EGF [93].…”

“…Neural stem cells from the adult subventricular zone can be expanded and maintained in vitro under the influence of fibroblast growth factor 2 (FGF2) and epidermal growth factor (EGF); these observations suggested that FGF2 and EGF might also act in vivo [84][85][86][87][88]. Indeed, knockout mice for FGF2 or transforming growth factor-α, a ligand for EGF receptor, exhibit decreased neurogenesis in the SVZ, and fewer neurons recruited to the olfactory bulb [89,90].…”

A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

“…Other astroglial-inducing factors, such as leukemia inhibitory factor (LIF), Notch-Delta, and basic fibroblast growth factor (bFGF) can initiate the astrocyte differentiation program only in E15 or older cortical progenitors, not in early (for example, E11), neurogenic progenitors 8,[13][14][15][16][17][18][19] . In E11 CNS neural progenitors, both Notch-Delta and bFGF function instead as pro-proliferation and anti-differentiation factors 15,18,[20][21][22] .LIF-induced Jak-STAT signaling is a critical part of the astrogliogenic machinery 23,24 . Mouse knockout studies have demonstrated that genetic deficiency in major components of this pathway, including LIF, its receptors LIFRβ and gp130, or the signaling molecules STAT1/3, leads to impaired astroglial differentiation [25][26][27] (Supplementary Fig.…”

Influence of age on the response to fibroblast growth factor-2 treatment in a rat model of stroke

“…Moreover, infusion of FGF-2 into the lateral ventricle of adult rats stimulates neurogenesis in the SVZ and increases the number of neurons migrating from SVZ to the olfactory bulb (Kuhn et al, 1997). Although basal and stroke-induced (Jin et al, 2004) neurogenesis decline with age, neuronal precursors in the SVZ retain the ability to respond to FGF-2 with an increase in neuronal proliferation (Jin et al, 2003).…”