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Transcript profiling of different types of multiple sclerosis lesions yields FGF1 as a promoter of remyelination.

Mohan H, Friese A, Albrecht S, Krumbholz M, Elliott CL, Arthur A, Menon R, Farina C, Junker A, Stadelmann C, Barnett SC, Huitinga I, Wekerle H, Hohlfeld R, Lassmann H, Kuhlmann T, Linington C, Meinl E - Acta Neuropathol Commun (2014)

Bottom Line: We dissected remyelinated, demyelinated active, and demyelinated inactive white matter MS lesions, and compared transcript levels of myelination and inflammation-related genes using quantitative PCR on customized TaqMan Low Density Arrays.In remyelinated lesions, fibroblast growth factor (FGF) 1 was the most abundant of all analyzed myelination-regulating factors, showed a trend towards higher expression as compared to demyelinated lesions and was significantly higher than in control white matter.Two MS tissue blocks comprised lesions with adjacent de- and remyelinated areas and FGF1 expression was higher in the remyelinated rim compared to the demyelinated lesion core.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, Marchioninistraße 15, D-81377, Munich, Germany. hema.mohan@ukmuenster.de.

ABSTRACT
Chronic demyelination is a pathological hallmark of multiple sclerosis (MS). Only a minority of MS lesions remyelinates completely. Enhancing remyelination is, therefore, a major aim of future MS therapies. Here we took a novel approach to identify factors that may inhibit or support endogenous remyelination in MS. We dissected remyelinated, demyelinated active, and demyelinated inactive white matter MS lesions, and compared transcript levels of myelination and inflammation-related genes using quantitative PCR on customized TaqMan Low Density Arrays. In remyelinated lesions, fibroblast growth factor (FGF) 1 was the most abundant of all analyzed myelination-regulating factors, showed a trend towards higher expression as compared to demyelinated lesions and was significantly higher than in control white matter. Two MS tissue blocks comprised lesions with adjacent de- and remyelinated areas and FGF1 expression was higher in the remyelinated rim compared to the demyelinated lesion core. In functional experiments, FGF1 accelerated developmental myelination in dissociated mixed cultures and promoted remyelination in slice cultures, whereas it decelerated differentiation of purified primary oligodendrocytes, suggesting that promotion of remyelination by FGF1 is based on an indirect mechanism. The analysis of human astrocyte responses to FGF1 by genome wide expression profiling showed that FGF1 induced the expression of the chemokine CXCL8 and leukemia inhibitory factor, two factors implicated in recruitment of oligodendrocytes and promotion of remyelination. Together, this study presents a transcript profiling of remyelinated MS lesions and identified FGF1 as a promoter of remyelination. Modulation of FGF family members might improve myelin repair in MS.

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FGF1 deceleratesdifferentiation of monocultured oligodendrocytes. (a) FGF1 does not affect proliferation of primary murine OPCs but (b) decelerates the differentiation into myelinating oligodendrocytes as determined by morphology; Two-way ANOVA with Bonferroni post correction **p < 0.01; *p < 0.05. The expression of myelin-associated genes was assessed by qPCR on samples from OPCs (6 h), immature (24 h) and mature cells (48 h). The expression levels of (c)Mbp, (d)Mag and in (e)Mog are reduced due to increasing FGF1 concentrations; one-way ANOVA with Bonferroni post correction *** p < 0.001 **P < 0.01; *P = <0.05; error bars represent SEM from three independent experiments.
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Fig7: FGF1 deceleratesdifferentiation of monocultured oligodendrocytes. (a) FGF1 does not affect proliferation of primary murine OPCs but (b) decelerates the differentiation into myelinating oligodendrocytes as determined by morphology; Two-way ANOVA with Bonferroni post correction **p < 0.01; *p < 0.05. The expression of myelin-associated genes was assessed by qPCR on samples from OPCs (6 h), immature (24 h) and mature cells (48 h). The expression levels of (c)Mbp, (d)Mag and in (e)Mog are reduced due to increasing FGF1 concentrations; one-way ANOVA with Bonferroni post correction *** p < 0.001 **P < 0.01; *P = <0.05; error bars represent SEM from three independent experiments.

Mentions: To determine the effect of FGF1 on the proliferation of monocultured oligodendroglial cells we cultured OPCs in the presence of PDGF-AA, NT3 and different concentrations of FGF1 for 24 or 48 h. No significant influence on the proliferation capacity of OPCs after 24 and 48 h compared to controls could be shown by BrdU assays (Figure 7a). To analyse effects of FGF1 on oligodendroglial differentiation, different concentrations of FGF1 were added to differentiating oligodendrocytes for up to 48 h. The differentiation of oligodendrocytes was analyzed using morphological parameters as well as the mRNA expression levels of several genes coding for myelin proteins. Addition of FGF1 for 48 h decreased significantly the number of mature oligodendrocytes characterized by multiple processes and complex branching (Figure 7b). To further examine the effect on oligodendroglial differentiation, we analyzed the mRNA expression levels of myelin proteins (Mbp, Mag, and Mog) at different time points. The expression levels of all genes were significantly downregulated after exposure to FGF1 (Figure 7c-e).Figure 7


Transcript profiling of different types of multiple sclerosis lesions yields FGF1 as a promoter of remyelination.

Mohan H, Friese A, Albrecht S, Krumbholz M, Elliott CL, Arthur A, Menon R, Farina C, Junker A, Stadelmann C, Barnett SC, Huitinga I, Wekerle H, Hohlfeld R, Lassmann H, Kuhlmann T, Linington C, Meinl E - Acta Neuropathol Commun (2014)

FGF1 deceleratesdifferentiation of monocultured oligodendrocytes. (a) FGF1 does not affect proliferation of primary murine OPCs but (b) decelerates the differentiation into myelinating oligodendrocytes as determined by morphology; Two-way ANOVA with Bonferroni post correction **p < 0.01; *p < 0.05. The expression of myelin-associated genes was assessed by qPCR on samples from OPCs (6 h), immature (24 h) and mature cells (48 h). The expression levels of (c)Mbp, (d)Mag and in (e)Mog are reduced due to increasing FGF1 concentrations; one-way ANOVA with Bonferroni post correction *** p < 0.001 **P < 0.01; *P = <0.05; error bars represent SEM from three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359505&req=5

Fig7: FGF1 deceleratesdifferentiation of monocultured oligodendrocytes. (a) FGF1 does not affect proliferation of primary murine OPCs but (b) decelerates the differentiation into myelinating oligodendrocytes as determined by morphology; Two-way ANOVA with Bonferroni post correction **p < 0.01; *p < 0.05. The expression of myelin-associated genes was assessed by qPCR on samples from OPCs (6 h), immature (24 h) and mature cells (48 h). The expression levels of (c)Mbp, (d)Mag and in (e)Mog are reduced due to increasing FGF1 concentrations; one-way ANOVA with Bonferroni post correction *** p < 0.001 **P < 0.01; *P = <0.05; error bars represent SEM from three independent experiments.
Mentions: To determine the effect of FGF1 on the proliferation of monocultured oligodendroglial cells we cultured OPCs in the presence of PDGF-AA, NT3 and different concentrations of FGF1 for 24 or 48 h. No significant influence on the proliferation capacity of OPCs after 24 and 48 h compared to controls could be shown by BrdU assays (Figure 7a). To analyse effects of FGF1 on oligodendroglial differentiation, different concentrations of FGF1 were added to differentiating oligodendrocytes for up to 48 h. The differentiation of oligodendrocytes was analyzed using morphological parameters as well as the mRNA expression levels of several genes coding for myelin proteins. Addition of FGF1 for 48 h decreased significantly the number of mature oligodendrocytes characterized by multiple processes and complex branching (Figure 7b). To further examine the effect on oligodendroglial differentiation, we analyzed the mRNA expression levels of myelin proteins (Mbp, Mag, and Mog) at different time points. The expression levels of all genes were significantly downregulated after exposure to FGF1 (Figure 7c-e).Figure 7

Bottom Line: We dissected remyelinated, demyelinated active, and demyelinated inactive white matter MS lesions, and compared transcript levels of myelination and inflammation-related genes using quantitative PCR on customized TaqMan Low Density Arrays.In remyelinated lesions, fibroblast growth factor (FGF) 1 was the most abundant of all analyzed myelination-regulating factors, showed a trend towards higher expression as compared to demyelinated lesions and was significantly higher than in control white matter.Two MS tissue blocks comprised lesions with adjacent de- and remyelinated areas and FGF1 expression was higher in the remyelinated rim compared to the demyelinated lesion core.

View Article: PubMed Central - PubMed

Affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, Marchioninistraße 15, D-81377, Munich, Germany. hema.mohan@ukmuenster.de.

ABSTRACT
Chronic demyelination is a pathological hallmark of multiple sclerosis (MS). Only a minority of MS lesions remyelinates completely. Enhancing remyelination is, therefore, a major aim of future MS therapies. Here we took a novel approach to identify factors that may inhibit or support endogenous remyelination in MS. We dissected remyelinated, demyelinated active, and demyelinated inactive white matter MS lesions, and compared transcript levels of myelination and inflammation-related genes using quantitative PCR on customized TaqMan Low Density Arrays. In remyelinated lesions, fibroblast growth factor (FGF) 1 was the most abundant of all analyzed myelination-regulating factors, showed a trend towards higher expression as compared to demyelinated lesions and was significantly higher than in control white matter. Two MS tissue blocks comprised lesions with adjacent de- and remyelinated areas and FGF1 expression was higher in the remyelinated rim compared to the demyelinated lesion core. In functional experiments, FGF1 accelerated developmental myelination in dissociated mixed cultures and promoted remyelination in slice cultures, whereas it decelerated differentiation of purified primary oligodendrocytes, suggesting that promotion of remyelination by FGF1 is based on an indirect mechanism. The analysis of human astrocyte responses to FGF1 by genome wide expression profiling showed that FGF1 induced the expression of the chemokine CXCL8 and leukemia inhibitory factor, two factors implicated in recruitment of oligodendrocytes and promotion of remyelination. Together, this study presents a transcript profiling of remyelinated MS lesions and identified FGF1 as a promoter of remyelination. Modulation of FGF family members might improve myelin repair in MS.

Show MeSH
Related in: MedlinePlus