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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 expression is elevated in remyelinated lesions. (a)FGF1 gene expression was analyzed by quantitative PCR TLDA relative to GAPDH in individual lesion areas (Re: remyelinated, De: demyelinated inactive, Active: actively demyelinating areas) and control white matter specimens (Ctrl.). Each symbol represents a single dissected area. Medians (bars) and 1st/3rd quartiles (boxes) are shown. Whiskers extend to the range up to 1.5 times of the interquartile range; values beyond were regarded as outliers. We noted one outlier in the six analyzed demyelinated inactive lesions, but we cannot explain why this one lesion had a higher FGF1 level than all others. Regarding the primary topic of remyelination in this study, we compared the remyelinated lesions with the other groups of tissue specimens; Mann–Whitney U test showed a significant difference between the remyelinated areas and controls (p < 0.01), while the differences between remyelinated vs. demyelinated inactive areas (p = 0.1) and remyelinated vs. actively demyelinating areas (p = 0.2) did not reach statistical significance. (b-d) In two blocks, adjacent de- and remyelinated areas were present within the same lesion and excised for quantitative PCR TLDA analysis (labelled as Block 1 and 2 for Figure 2a-e). FGF1 expression normalized to GAPDH is shown. Fold-changes of FGF1 expression between the re- and demyelinated areas in each block were calculated for the different housekeeping genes. The geometric mean of these fold-changes obtained by normalization to the three housekeeping genes was 2.1× for block 1 and 4.1× for block 2.
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Fig2: FGF1 expression is elevated in remyelinated lesions. (a)FGF1 gene expression was analyzed by quantitative PCR TLDA relative to GAPDH in individual lesion areas (Re: remyelinated, De: demyelinated inactive, Active: actively demyelinating areas) and control white matter specimens (Ctrl.). Each symbol represents a single dissected area. Medians (bars) and 1st/3rd quartiles (boxes) are shown. Whiskers extend to the range up to 1.5 times of the interquartile range; values beyond were regarded as outliers. We noted one outlier in the six analyzed demyelinated inactive lesions, but we cannot explain why this one lesion had a higher FGF1 level than all others. Regarding the primary topic of remyelination in this study, we compared the remyelinated lesions with the other groups of tissue specimens; Mann–Whitney U test showed a significant difference between the remyelinated areas and controls (p < 0.01), while the differences between remyelinated vs. demyelinated inactive areas (p = 0.1) and remyelinated vs. actively demyelinating areas (p = 0.2) did not reach statistical significance. (b-d) In two blocks, adjacent de- and remyelinated areas were present within the same lesion and excised for quantitative PCR TLDA analysis (labelled as Block 1 and 2 for Figure 2a-e). FGF1 expression normalized to GAPDH is shown. Fold-changes of FGF1 expression between the re- and demyelinated areas in each block were calculated for the different housekeeping genes. The geometric mean of these fold-changes obtained by normalization to the three housekeeping genes was 2.1× for block 1 and 4.1× for block 2.

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)

FGF1 expression is elevated in remyelinated lesions. (a)FGF1 gene expression was analyzed by quantitative PCR TLDA relative to GAPDH in individual lesion areas (Re: remyelinated, De: demyelinated inactive, Active: actively demyelinating areas) and control white matter specimens (Ctrl.). Each symbol represents a single dissected area. Medians (bars) and 1st/3rd quartiles (boxes) are shown. Whiskers extend to the range up to 1.5 times of the interquartile range; values beyond were regarded as outliers. We noted one outlier in the six analyzed demyelinated inactive lesions, but we cannot explain why this one lesion had a higher FGF1 level than all others. Regarding the primary topic of remyelination in this study, we compared the remyelinated lesions with the other groups of tissue specimens; Mann–Whitney U test showed a significant difference between the remyelinated areas and controls (p < 0.01), while the differences between remyelinated vs. demyelinated inactive areas (p = 0.1) and remyelinated vs. actively demyelinating areas (p = 0.2) did not reach statistical significance. (b-d) In two blocks, adjacent de- and remyelinated areas were present within the same lesion and excised for quantitative PCR TLDA analysis (labelled as Block 1 and 2 for Figure 2a-e). FGF1 expression normalized to GAPDH is shown. Fold-changes of FGF1 expression between the re- and demyelinated areas in each block were calculated for the different housekeeping genes. The geometric mean of these fold-changes obtained by normalization to the three housekeeping genes was 2.1× for block 1 and 4.1× for block 2.
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Fig2: FGF1 expression is elevated in remyelinated lesions. (a)FGF1 gene expression was analyzed by quantitative PCR TLDA relative to GAPDH in individual lesion areas (Re: remyelinated, De: demyelinated inactive, Active: actively demyelinating areas) and control white matter specimens (Ctrl.). Each symbol represents a single dissected area. Medians (bars) and 1st/3rd quartiles (boxes) are shown. Whiskers extend to the range up to 1.5 times of the interquartile range; values beyond were regarded as outliers. We noted one outlier in the six analyzed demyelinated inactive lesions, but we cannot explain why this one lesion had a higher FGF1 level than all others. Regarding the primary topic of remyelination in this study, we compared the remyelinated lesions with the other groups of tissue specimens; Mann–Whitney U test showed a significant difference between the remyelinated areas and controls (p < 0.01), while the differences between remyelinated vs. demyelinated inactive areas (p = 0.1) and remyelinated vs. actively demyelinating areas (p = 0.2) did not reach statistical significance. (b-d) In two blocks, adjacent de- and remyelinated areas were present within the same lesion and excised for quantitative PCR TLDA analysis (labelled as Block 1 and 2 for Figure 2a-e). FGF1 expression normalized to GAPDH is shown. Fold-changes of FGF1 expression between the re- and demyelinated areas in each block were calculated for the different housekeeping genes. The geometric mean of these fold-changes obtained by normalization to the three housekeeping genes was 2.1× for block 1 and 4.1× for block 2.
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