Acute and chronic demyelinated CNS lesions exhibit opposite elastic properties

Mateusz M Urbanski,Matthew B Brendel,Carmen V Melendez-Vasquez

doi:10.1038/s41598-018-37745-7

Abstract

Increased deposition of extracellular matrix (ECM) is a known inhibitor of axonal regrowth and remyelination. Recent in vitro studies have demonstrated that oligodendrocyte differentiation is impacted by the physical properties of the ECM. However, characterization of the mechanical properties of the healthy and injured CNS myelin is challenging, and has largely relied on non-invasive, low-resolution methods. To address this, we have employed atomic force microscopy to perform micro-indentation measurements of demyelinated tissue at cellular scale. Analysis of mouse and human demyelinated brains indicate that acute demyelination results in decreased tissue stiffness that recovers with remyelination; while chronic demyelination is characterized by increased tissue stiffness, which correlates with augmented ECM deposition. Thus, changes in the mechanical properties of the acutely (softer) or chronically (stiffer) demyelinated brain might contribute to differences in their regenerative capacity. Our findings are relevant to the optimization of cell-based therapies aimed at promoting CNS regeneration and remyelination.

Highlights

Despite the presence of oligodendrocyte progenitor cells (OPC) capable of regenerating myelin after its loss, chronic multiple sclerosis (MS) lesions in the brain and the spinal cord are characterized by remyelination failure
Schregel et al.[19] examined the elastic properties of the mouse corpus callosum during a 12-week course of cuprizone induced demyelination. Their results showed an initial increase in stiffness, followed by a decrease at the 12-week time point associated with remyelination failure and steady increase in extracellular matrix (ECM) deposition
It is possible that ECM deposited as a result of demyelinating insult is not structurally coherent, increased ECM deposition generally correlates with increased tissue stiffness, as seen in injury-induced tissue fibrosis and tumor progression[23,24,25,26]

Summary

Introduction

Despite the presence of oligodendrocyte progenitor cells (OPC) capable of regenerating myelin after its loss, chronic multiple sclerosis (MS) lesions in the brain and the spinal cord are characterized by remyelination failure. Schregel et al.[19] examined the elastic properties of the mouse corpus callosum during a 12-week course of cuprizone induced demyelination Their results showed an initial increase in stiffness, followed by a decrease at the 12-week time point associated with remyelination failure and steady increase in ECM deposition. It is possible that ECM deposited as a result of demyelinating insult is not structurally coherent, increased ECM deposition generally correlates with increased tissue stiffness, as seen in injury-induced tissue fibrosis and tumor progression[23,24,25,26] This apparent contradiction may be explained by the low spatial resolution of the non-invasive MRE approach. Since many of the ECM aggregates present in demyelinated lesions appear to be of cellular or sub-cellular size[15,27], it is likely that lower-resolution methods understate or overlook their mechanical contribution

Methods

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Conclusion