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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 is expressed in re- and demyelinated lesions as well as in neurons and oligodendroglia in control brain and NAWM. (a) LFB staining of an MS tissue specimen with demyelinated (De), remyelinated (Re) lesion areas along with normal appearing white mater (NAWM) and gray matter (GM). The FGF staining was more prominent in the remyelinated area (b) compared to the chronic inactive demyelinated area (c). In control brain, FGF1 staining was detected in neurons of gray matter (d) and cells appearing as oligodendrocytes in white matter (e, f). Scale bars: 20 μm.
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Fig3: FGF1 is expressed in re- and demyelinated lesions as well as in neurons and oligodendroglia in control brain and NAWM. (a) LFB staining of an MS tissue specimen with demyelinated (De), remyelinated (Re) lesion areas along with normal appearing white mater (NAWM) and gray matter (GM). The FGF staining was more prominent in the remyelinated area (b) compared to the chronic inactive demyelinated area (c). In control brain, FGF1 staining was detected in neurons of gray matter (d) and cells appearing as oligodendrocytes in white matter (e, f). Scale bars: 20 μm.

Mentions: Accordingly, FGF1 staining was more prominent in the re- compared to the demyelinated lesion area (Figure 3a-c). Analyzing control brain for FGF1 expression, we found cortical neurons to be FGF1 positive (Figure 3d). Furthermore, FGF1 staining was detected in cells which, according to their morphology, could be oligodendroglia (Figure 3e-f). These FGF1-positive oligodendroglia could also be detected in NAWM of MS brain (data not shown). Double staining of FGF1 and GFAP revealed astrocytes in remyelinated lesions to be FGF1 positive (Figure 4a). In contrast, reactive astrocytes detected in NAWM surrounding the lesion areas were FGF1 negative (Figure 4b). In active lesions we detected subsets of microglia/macrophages to be FGF1 positive (Figure 4c). Furthermore, subsets of B and T cells present in perivascular cuffs displayed FGF1 staining (Figure 4d, e). Together, our staining localized FGF1 to astrocytes, oligodendrocytes, microglia/macrophages and infiltrating lymphocytes, but we cannot conclude from our staining which cells are the major sources and why it is produced.Figure 3


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 is expressed in re- and demyelinated lesions as well as in neurons and oligodendroglia in control brain and NAWM. (a) LFB staining of an MS tissue specimen with demyelinated (De), remyelinated (Re) lesion areas along with normal appearing white mater (NAWM) and gray matter (GM). The FGF staining was more prominent in the remyelinated area (b) compared to the chronic inactive demyelinated area (c). In control brain, FGF1 staining was detected in neurons of gray matter (d) and cells appearing as oligodendrocytes in white matter (e, f). Scale bars: 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: FGF1 is expressed in re- and demyelinated lesions as well as in neurons and oligodendroglia in control brain and NAWM. (a) LFB staining of an MS tissue specimen with demyelinated (De), remyelinated (Re) lesion areas along with normal appearing white mater (NAWM) and gray matter (GM). The FGF staining was more prominent in the remyelinated area (b) compared to the chronic inactive demyelinated area (c). In control brain, FGF1 staining was detected in neurons of gray matter (d) and cells appearing as oligodendrocytes in white matter (e, f). Scale bars: 20 μm.
Mentions: Accordingly, FGF1 staining was more prominent in the re- compared to the demyelinated lesion area (Figure 3a-c). Analyzing control brain for FGF1 expression, we found cortical neurons to be FGF1 positive (Figure 3d). Furthermore, FGF1 staining was detected in cells which, according to their morphology, could be oligodendroglia (Figure 3e-f). These FGF1-positive oligodendroglia could also be detected in NAWM of MS brain (data not shown). Double staining of FGF1 and GFAP revealed astrocytes in remyelinated lesions to be FGF1 positive (Figure 4a). In contrast, reactive astrocytes detected in NAWM surrounding the lesion areas were FGF1 negative (Figure 4b). In active lesions we detected subsets of microglia/macrophages to be FGF1 positive (Figure 4c). Furthermore, subsets of B and T cells present in perivascular cuffs displayed FGF1 staining (Figure 4d, e). Together, our staining localized FGF1 to astrocytes, oligodendrocytes, microglia/macrophages and infiltrating lymphocytes, but we cannot conclude from our staining which cells are the major sources and why it is produced.Figure 3

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