Absence of Fibroblast Growth Factor 2 Promotes Oligodendroglial Repopulation of Demyelinated White Matter

Abstract

This study takes advantage of fibroblast growth factor 2 (FGF2) knock-out mice to determine the contribution of FGF2 to the regeneration of oligodendrocytes in the adult CNS. The role of FGF2 during spontaneous remyelination was examined using two complementary mouse models of experimental demyelination. The murine hepatitis virus strain A59 (MHV-A59) model produces focal areas of spinal cord demyelination with inflammation. The cuprizone neurotoxicant model causes extensive corpus callosum demyelination without a lymphocytic cell response. In both models, FGF2 expression is upregulated in areas of demyelination in wild-type mice. Surprisingly, in both models, oligodendrocyte repopulation of demyelinated white matter was significantly increased in FGF2 -/- mice compared with wild-type mice and even surpassed the oligodendrocyte density of nonlesioned mice. This dramatic result indicated that the absence of FGF2 promoted oligodendrocyte regeneration, possibly by enhancing oligodendrocyte progenitor proliferation and/or differentiation. FGF2 -/- and +/+ mice had similar oligodendrocyte progenitor densities in normal adult CNS, as well as similar progenitor proliferation and accumulation during demyelination. To directly analyze progenitor differentiation, glial cultures from spinal cords of wild-type mice undergoing remyelination after MHV-A59 demyelination were treated for 3 d with either exogenous FGF2 or an FGF2 neutralizing antibody. Elevating FGF2 favored progenitor proliferation, whereas attenuating endogenous FGF2 activity promoted the differentiation of progenitors into oligodendrocytes. These in vitro results are consistent with enhanced progenitor differentiation in FGF2 -/- mice. These studies demonstrate that the FGF2 genotype regulates oligodendrocyte regeneration and that FGF2 appears to inhibit oligodendrocyte lineage differentiation during remyelination.

Interaction of fibroblast growth factor 2 (FGF2) and notch signaling components in inhibition of oligodendrocyte progenitor (OP) differentiation

“…Furthermore, pharmacological inhibition of notch signaling may enhance remyelination [9]. Our analysis of FGF2 null mice indicated improved remyelination associated with removal of FGF2 inhibition of OP differentiation, while we did not find evidence of an FGF2 effect on OP proliferation in vivo [2,3,15].…”

“…Our work in FGF2 null mice demonstrated that FGF2 inhibits differentiation of oligodendrocyte progenitor (OP) cells into myelinating oligodendrocytes during both development and remyelination [3,14,15]. Importantly, FGF2 limits effective remyelination following chronic demyelination [2].…”

Growth factor regulation of remyelination: behind the growing interest in endogenous cell repair of the CNS

“…Areas of acute and chronic demyelination have increased expression of FGF2 ligand and FGF receptors [11,26,36,37]. In contrast with predictions from in vitro studies, OP proliferation in demyelinated lesions was not impaired in FGF2-null mice, indicating that the potential for FGF2 to act as an OP mitogen may not be a significant role of endogenous FGF2 in vivo during demyelination [37]. Studies testing elevated levels of FGF2 indicate a potential mitogenic role of FGF2 signaling, which may be distinct from the response elicited by endogenous FGF2 in lesioned white matter.…”

“…With cuprizone demyelination of the corpus callosum, toxicity is primarily within mature oligodendrocytes, presumably because of the metabolic load of maintaining the extensive myelin membranes [39]. During cuprizone treatment, OP populations proliferate both within the demyelinated areas of white matter and in the adjacent SVZ [15,29,37]. By contrast, demyelination models of lysolecithin or ethidium bromide injection have significant loss of OP cells within lesion areas [40,41].…”

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

“…56 FGF2 even stimulated post-mitotic oligodendrocytes to reenter the S-phase of the cell cycle, while FGF2 knockout enhanced OPCs differentiation and promoted oligodendrocyte repopulation in the demyelinated area following CPZ insult. 57,58 Moreover, activation of microglia by CPZ led to increased growth factor production and secretion of pro-inflammatory cytokines such as TNFa (tumor necrosis factor a) and IFNg(interferon-g). [3][4][5]59,60 The latter (IFN-g)was shown to inhibit cell cycle exit in oligodendrocyte progenitor cells and attenuate MBP expression.…”