Polarizing receptor activation dissociates fibroblast growth factor 2 mediated inhibition of myelination from its neuroprotective potential

Katja Thümmler,Maren Lindner,Julia M Edgar,John J Cole,Thomas Zeis,Eran Rom,Steve Mücklisch,Sarah Brunner,Avner Yayon,Nicole Schaeren-Wiemers,Christopher Linington,Diana Arseni

doi:10.1186/s40478-019-0864-6

Abstract

Fibroblast growth factor (FGF) signaling contributes to failure of remyelination in multiple sclerosis, but targeting this therapeutically is complicated by its functional pleiotropy. We now identify FGF2 as a factor up-regulated by astrocytes in active inflammatory lesions that disrupts myelination via FGF receptor 2 (FGFR2) mediated activation of Wingless (Wnt) signaling; pharmacological inhibition of Wnt being sufficient to abrogate inhibition of myelination by FGF2 in tissue culture. Using a novel FGFR1-selective agonist (F2 V2) generated by deleting the N-terminal 26 amino acids of FGF2 we demonstrate polarizing signal transduction to favor FGFR1 abrogates FGF mediated inhibition of myelination but retains its ability to induce expression of pro-myelinating and immunomodulatory factors that include Cd93, Lif, Il11, Hbegf, Cxcl1 and Timp1. Our data provide new insights into the mechanistic basis of remyelination failure in MS and identify selective activation of FGFR1 as a novel strategy to induce a neuroprotective signaling environment in multiple sclerosis and other neurological diseases.

Highlights

Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system (CNS) in which repeated episodes of inflammatory demyelination result in persistently demyelinated plaques of gliotic scar tissue associated with varying degrees of axonal injury and loss
As previous studies indicate the mitogenic potential of FGF2 is FGFR1 dependent [25] we investigated the effects of F2 V2, a novel FGFR1-selective agonist, on oligodendrogenesis and myelination in cultures derived from embryonic spinal cord; an in vitro model that replicates the cellular complexity of the CNS and allows identification of direct and “off target” effects on oligodendrocyte progenitor cells (OPC) biology [51]
To investigate how FGF2-dependent mechanisms contribute to lesion development in MS we first mapped its expression in lesions and normal appearing white matter (NAWM) by in situ hybridization and immunohistochemistry

Summary

Introduction

Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system (CNS) in which repeated episodes of inflammatory demyelination result in persistently demyelinated plaques of gliotic scar tissue associated with varying degrees of axonal injury and loss. This axonal pathology is the underlying cause of chronic disability in MS and is intimately associated with demyelination.

Methods

Results

Conclusion