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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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Related in: MedlinePlus

Oligodendrocyte regulators are differentially expressed in various lesion types. MS lesions were dissected from frozen tissue and the expression level of the indicated mediators regulating oligodendrocytes were determined by qPCR. The absolute expression levels are given in terms of % GAPDH. Displayed is the mean of 6 normal white matter specimens, 6 demyelinated inactive, 4 demyelinated active, and 4 remyelinated lesion areas.
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Fig1: Oligodendrocyte regulators are differentially expressed in various lesion types. MS lesions were dissected from frozen tissue and the expression level of the indicated mediators regulating oligodendrocytes were determined by qPCR. The absolute expression levels are given in terms of % GAPDH. Displayed is the mean of 6 normal white matter specimens, 6 demyelinated inactive, 4 demyelinated active, and 4 remyelinated lesion areas.

Mentions: FGF1 was the most abundant FGF both in the white matter of the control brain and in the white matter of MS lesions (Figure 1, Table 2). Further, FGF1 had the highest transcript level of all the analyzed myelination-related factors (Figure 1, Table 2) and was therefore further studied in detail. In remyelinated lesions, FGF1 showed a trend towards higher expression compared to demyelinated lesions and was significantly higher expressed than in control white matter (Figure 1, Figure 2a,b). We could directly compare FGF1 expression in two tissue blocks with de- and remyelinated areas within the same lesion: in both blocks FGF1 transcript levels were higher in the dissected remyelinated areas compared to the demyelinated lesion core (Figure 2b-e).Figure 1


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)

Oligodendrocyte regulators are differentially expressed in various lesion types. MS lesions were dissected from frozen tissue and the expression level of the indicated mediators regulating oligodendrocytes were determined by qPCR. The absolute expression levels are given in terms of % GAPDH. Displayed is the mean of 6 normal white matter specimens, 6 demyelinated inactive, 4 demyelinated active, and 4 remyelinated lesion areas.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Oligodendrocyte regulators are differentially expressed in various lesion types. MS lesions were dissected from frozen tissue and the expression level of the indicated mediators regulating oligodendrocytes were determined by qPCR. The absolute expression levels are given in terms of % GAPDH. Displayed is the mean of 6 normal white matter specimens, 6 demyelinated inactive, 4 demyelinated active, and 4 remyelinated lesion areas.
Mentions: FGF1 was the most abundant FGF both in the white matter of the control brain and in the white matter of MS lesions (Figure 1, Table 2). Further, FGF1 had the highest transcript level of all the analyzed myelination-related factors (Figure 1, Table 2) and was therefore further studied in detail. In remyelinated lesions, FGF1 showed a trend towards higher expression compared to demyelinated lesions and was significantly higher expressed than in control white matter (Figure 1, Figure 2a,b). We could directly compare FGF1 expression in two tissue blocks with de- and remyelinated areas within the same lesion: in both blocks FGF1 transcript levels were higher in the dissected remyelinated areas compared to the demyelinated lesion core (Figure 2b-e).Figure 1

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