Endogenous cell repair of chronic demyelination.
In multiple sclerosis lesions, remyelination typically fails with repeated or chronic demyelinating episodes and results in neurologic disability. Acute demyelination models in rodents typically exhibit robust spontaneous remyelination that prevents appropriate evaluation of strategies for improving conditions of insufficient remyelination. In the current study, we used a mouse model of chronic demyelination induced by continuous ingestion of 0.2% cuprizone for 12 weeks. This chronic process depleted the oligodendrocyte progenitor population and impaired oligodendrocyte regeneration. Remyelination remained limited after removal of cuprizone from the diet. Fibroblast growth factor 2 (FGF2) expression was persistently increased in the corpus callosum of chronically demyelinated mice as compared with nonlesioned mice. We used FGF2 mice to determine whether removal of endogenous FGF2 promoted remyelination of chronically demyelinated areas. Wild-type and FGF2 mice exhibited similar demyelination during chronic cuprizone treatment. Importantly, in contrast to wild-type mice, the FGF2 mice spontaneously remyelinated completely during the recovery period after chronic demyelination. Increased remyelination in FGF2 mice correlated with enhanced oligodendroglial regeneration. FGF2 genotype did not alter the density of oligodendrocyte progenitor cells or proliferating cells after chronic demyelination. These findings indicate that attenuating FGF2 created a sufficiently permissive lesion environment for endogenous cells to effectively remyelinate viable axons even after chronic demyelination.
Armstrong
Regina C
RC
Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. 20814, USA. rarmstrong@usuhs.mil
Le
Tuan Q
TQ
Flint
Nicole C
NC
Vana
Adam C
AC
Zhou
Yong-Xing
YX
D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D003337:Corpus Callosum / Q000166:cytology / Q000502:physiology; D003471:Cuprizone / Q000494:pharmacology; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology*; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D002614:Chelating Agents; D016222:Fibroblast Growth Factor 2; D003471:Cuprizone