Antibody-mediated neutralization of myelin-associated EphrinB3 accelerates CNS remyelination.

Yasir A Syed,Don Mahad,Wiebke Möbius,Franziska Foss,Aycan Sentürk,Klaus-A Nave,Chao Zhao,Kathryn Lilley,Amparo Acker-Palmer,Robin J M Franklin,Gert Lubec,Friedrich Altmann,Mark R N Kotter

doi:10.1007/s00401-015-1521-1

Abstract

Remyelination in multiple sclerosis (MS) lesions often remains incomplete despite the presence of oligodendrocyte progenitor cells (OPCs). Amongst other factors, successful remyelination depends on the phagocytic clearance of myelin debris. However, the proteins in myelin debris that act as potent and selective inhibitors on OPC differentiation and inhibit CNS remyelination remain unknown. Here, we identify the transmembrane signalling protein EphrinB3 as important mediator of this inhibition, using a protein analytical approach in combination with a primary rodent OPC assay. In the presence of EphrinB3, OPCs fail to differentiate. In a rat model of remyelination, infusion of EphrinB3 inhibits remyelination. In contrast, masking EphrinB3 epitopes using antibodies promotes remyelination. Finally, we identify EphrinB3 in MS lesions and demonstrate that MS lesion extracts inhibit OPC differentiation while antibody-mediated masking of EphrinB3 epitopes promotes it. Our findings suggest that EphrinB3 could be a target for therapies aiming at promoting remyelination in demyelinating disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1521-1) contains supplementary material, which is available to authorized users.

Highlights

Myelin sheaths are layered, lipid-rich structures that wrap around axons to mediate salutatory signal conduction along them and provide them with trophic support [38, 45]
Assessment of oligodendrocyte progenitor cells (OPCs) cultured for 48 h on PLL control, rat and human myelin substrates confirmed strongly inhibited expression of the early differentiation marker O4 and myelin basic protein (MBP), a protein expressed by mature oligodendrocytes
To assess transcriptional consequences of Ephrin signalling in OPCs, we investigated the expression of Nkx2.2, a functionally important transcription factor that is known to be up-regulated at the onset of OPC differentiation [19], but whose expression fails to increase in the presence of myelin extracts in vitro [48] and in vivo [28]

Summary

Introduction

Lipid-rich structures that wrap around axons to mediate salutatory signal conduction along them and provide them with trophic support [38, 45]. In the central nervous system (CNS), myelin sheaths are formed by oligodendrocytes [9]. In response to myelin degeneration, multipotent parenchymal progenitor cells called oligodendrocyte progenitor cells (OPCs) are activated and recruited to the damaged areas [22]. These can regenerate myelin to some extent, but the process is often incomplete [35], leaving axons permanently demyelinated and vulnerable to degeneration [6]

Methods

Results

Conclusion