In vivo actions of fibroblast growth factor-2 and insulin-like growth factor-I on oligodendrocyte development and myelination in the central nervous system

Abstract

The in vivo effects of fibroblast growth factor-2 (FGF-2) and insulin-like growth factor-I (IGF-I) on oligodendrocytes and CNS myelination were determined in the postnatal rat anterior medullary velum (AMV) following injection of both cytokines into the cerebrospinal fluid. Either FGF-2, IGF-I, or saline were administered via the lateral ventricle, twice daily commencing at postnatal day (P) 6. At P9, AMV were immunohistochemically labeled with the Rip antibody, to enable analysis of the numbers of myelin sheaths and of promyelinating and myelinating oligodendrocytes; promyelinating oligodendrocytes are a recognisable immature phenotype which express myelin-related proteins prior to forming myelin sheaths. In parallel experiments, AMV were treated for Western blot analysis to determine relative changes in expression of the myelin proteins 2', 3'-cyclic nucleotide 3'-phosphohydrolase (CNP) and myelin oligodendrocyte glycoprotein (MOG), which, respectively, characterise early and late stages of myelin maturation. In FGF-2-treated AMV, the number of promyelinating oligodendrocytes increased by 87% compared to saline-injected controls. The numbers of myelinating oligodendrocytes and myelin sheaths were not decreased, but conspicuous unmyelinated gaps within fibre tracts were indications of retarded myelination following FGF-2 treatment. Western blot analysis demonstrated decreased expression of CNP and a near-total loss of MOG, confirming that FGF-2 decreased myelin maturation. In contrast, IGF-I had no effect on the number of promyelinating oligodendrocytes, but increased the numbers of myelinating oligodendrocytes and myelin sheaths by 100% and 93%, respectively. Western blot analysis showed that the amount of CNP was increased following IGF-I treatment, correlating with the greater number of oligodendrocytes, but that MOG expression was lower than in controls, suggesting that the increased number of myelin sheaths in IGF-I was not matched by increased myelin maturation. The results provide in vivo evidence that FGF-2 and IGF-I control the numbers of oligodendrocytes in the brain and, respectively, retard and promote myelination.

Fibroblast growth factor-II gene therapy reverts the clinical course and the pathological signs of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice

“…19 Our results, along with preliminary observations indicating that repeated injection of the TH:bFGF vector partially abrogated the beneficial effect observed after a single vector injection (RF, personal comunication), support the concept that CNS short-term production of FGF-II by triple-mutant HSV-1 vectors may partially circumvent this therapy-threatening side-effect. The short-term CNS production of FGF-II (in the early phase of EAE) might have induced the migration and proliferation of oligodendrocyte precursors into demyelinated areas, and the 'physiologic' shut-off of the vector after 2-3 weeks, might have allowed 'remyelination' through the differentiation of the recruited progenitors into myelin-forming cells.…”

“…17,18 FGF-II is a neurotrophic growth factor able to promote migration and proliferation of oligodendrocyte precursor cells. 19 The intrathecal delivery into C57BL/6 mice with ongoing EAE of the TH:bFGF vector determined in situ short-term production of FGF-II leading to amelioration of clinical and pathological signs of EAE via a significant increase of the recruitment of oligodendrocyte precursors into CNS areas of demyelination.…”

Distinctive Properties of Human Adult Brain-Derived Myelin Progenitor Cells

“…This comparative analysis was performed after cells were maintained in culture for 5 to 7 days under relatively basal culture conditions supplemented with growth factors (bFGF and T3) that are considered to promote cell survival and proliferation rather than differentiation. 24,25 A small proportion (5 to 10%) of the adult A2B5 ϩ cell population morphologically distinct from the CD68 microglia expressed NG2 ϩ , which is found later in the OLG progenitor lineage than is A2B5, showing the persistence of the progenitor characteristic on these cells. This population was smaller than in fetal A2B5 ϩ cells (10 to 20% of cells).…”

FGF-2 and Anosmin-1 Are Selectively Expressed in Different Types of Multiple Sclerosis Lesions

“…One of the main mitogens for OPCs is FGF-2, which also acts as a motogenic or chemokinetic and chemotropic factor, in both cases acting via FGF receptor 1 (FGFR1) (Bögler et al, 1990;McKinnon et al, 1990;Goddard et al, 1999Goddard et al, , 2001Bribián et al, 2006). Thus, FGF-2 could be involved in oligodendrocyte responses during demyelination and remyelination, although the effects exerted by this growth factor have proven to be controversial (Ruffini et al, 2001;Butt and Dinsdale, 2005).…”