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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0168-9) contains supplementary material, which is available to authorized users.

Control of autoimmune CNS inflammation by astrocytes

“…A study by Mohan et al (111) suggest that CXCL8 and LIF are involved in the protective effects of FGF1: in a comparative screening of remyelinated and unmyelinated chronic MS lesions, the authors identified FGF1 as an putative inductor of remyelination. This hypothesis was further tested in vitro , when exposure of myelinating and organotypic cerebellar cultures showed enhanced myelination upon exposure to FGF1.…”

Prolonged stimulation of a brainstem raphe region attenuates experimental autoimmune encephalomyelitis

“…Multiple sclerosis (MS) is a chronic autoimmune disease characterized by localized destruction of the myelin sheets that enwrap and support axons of the central nervous system (CNS) (Friese et al, 2014; Mohan et al, 2014). The etiology is unknown and a satisfactory cure is elusive.…”

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

“…In contrast to its developmental regulation, the expression of LINGO-1 was found upregulated upon CNS injury as shown in spinal cord injury and human MS (Mi et al, 2004; Mohan et al, 2014; Satoh et al, 2007). There seems to be, however, some controversy on whether this upregulation occurs primarily on cells of the OLG lineage or in subpopulations of reactive astrocytes, macrophages/microglia and neurons (Satoh et al, 2007).…”

“…With regard to potential detrimental roles, injection of FGF-2 into the lateral ventricles of postnatal mice was found to delay myelination and lead to myelin breakdown (Goddard et al, 2001, 1999), and genetic deletion of Fgf2 or FGFR1 resulted in improved remyelination following experimental demyelination (Mierzwa et al, 2013; Tobin et al, 2011; Zhou et al, 2012). Conversely, however, FGF signaling has also been associated with successful remyelination (Mohan et al, 2014) and been described to potentiate myelin repair (Dehghan et al, 2012), provide neuroprotection (Rottlaender et al, 2011) and ameliorate clinical signs in a chronic EAE model (Ruffini et al, 2001). Recent data revealed that conditional deletion of both FGFR1 and FGFR2 in cells of the OLG lineage does not affect remyelination following acute myelination, but impairs OLG differentiation and/or survival in chronically demyelinated lesion, suggesting that cell-autonomous FGF signaling in OLGs is redundant during recovery of acute demyelinated lesions, but may facilitate regenerative processes in chronic demyelination (Furusho et al, 2015).…”