New strategy for brain repair in multiple sclerosis

Anti-inflammatory macrophages from the rat brain grown in the laboratory. The green represents an anti-inflammatory protein and the red represents a protein made by macrophages only. Credit Veronique Miron, MRC Centre for Regenerative Medicine
Anti-inflammatory macrophages from the rat brain grown in the laboratory. The green represents an anti-inflammatory protein and the red represents a protein made by macrophages only.
Image: Veronique Miron, MRC Centre for Regenerative Medicine

By: Veronique Miron

Multiple sclerosis (MS) affects over 400,000 people in the EU, causing problems with vision, movement and speech. In MS, the protective layer that surrounds nerves in the brain and spinal cord, called myelin, is destroyed. As the disease progresses, this damage often goes unchecked because the regenerative process for replacing myelin (‘remyelination’) fails. There are currently no approved therapies that tackle this problem by promoting remyelination. Researchers hope a new study published in the journal Nature Neuroscience will contribute to the development of new therapies by helping to explain how remyelination is controlled. The scientists studied immune cells called macrophages, which are involved in remyelination. They found that the macrophages must become anti-infammatory for remyelination to proceed, and identified a protein released by macrophages which encourages remyelination.Image removed.

What is the idea behind the study?

Remyelination can occur in early stages of multiple sclerosis, driven by cells called oligodendrocytes that make the new myelin. However, remyelination often fails as multiple sclerosis progresses. This failure leads to the damage of nerves which cannot regrow, causing the symptoms experienced by people with multiple sclerosis. All currently approved therapies for multiple sclerosis only slow disease progression by reducing myelin injury; these are not aimed at promoting remyelination. Thus, understanding what stimulates remyelination can lead to the discovery of biological molecules, cells or other factors that may be developed into regenerative therapies for the recovery of lost vision, movement or other functions in people with multiple sclerosis.

whats behind study
Image: Veronique Miron, MRC Centre for Regenerative Medicine

Previous studies have shown that immune cells called macrophages are involved in regeneration. Interestingly, anti-inflammatory (‘M2’) macrophages are required for the regeneration of skin and muscle. In a collaborative study between the University of Edinburgh’s MRC Centre for Regenerative Medicine and the University of Cambridge’s Wellcome Trust-MRC Cambridge Stem Cell Institute, scientists examined whether M2 macrophages were also needed for myelin regeneration. In doing so, they tested whether something was being released by M2 macrophages that could stimulate remyelination, in the hope that this could lead to the development of a new strategy for regeneration in people with multiple sclerosis.

What did the study show?

What did the study show
Image: Veronique Miron, MRC Centre for Regenerative Medicine

To ask whether M2 macrophages are present during remyelination, scientists carried out studies in mice, using them as a model to represent myelin damage and regeneration in the human body. The researchers found that M2 macrophages were present and that they increased in number at the start of remyelination, suggesting that these macrophages may control the regeneration process. It was already known that oligodendrocytes are the cells that normally make myelin in the brain and spinal cord, so the scientists asked whether M2 macrophages on their own are able to stimulate oligodendrocytes to start making myelin. To study this question, they exposed oligodendrocytes to proteins released by M2 macrophages in the laboratory. These proteins did promote more oligodendrocytes to make myelin.

The next question was whether remyelination could continue if the M2 macrophages were not available. The team eliminated these cells following myelin damage in experimental models. Without M2 macrophages, remyelination was dramatically reduced, indicating that M2 macrophages are needed for remyelination. Analysis of both mouse models of remyelination, and brain tissue from people with multiple sclerosis showed that numbers of M2 macrophages are high when remyelination is efficient, but lower when remyelination is poor.

The researchers then tested whether a protein called activin-A, which is produced by macrophages, contributes to the regenerative effects of M2 macrophages. Activin-A was present at very high levels in M2 macrophages as remyelination was starting, and addition of activin-A to oligodendrocytes in the laboratory stimulated them to make myelin. The researchers then blocked the effect of activin-A on oligodendrocytes after myelin injury, and found that this meant the M2 macrophages had a reduced ability to promote oligodendrocytes to make myelin.

In summary, this study shows that M2 macrophages release activin-A, which causes oligodendrocytes to make myelin, a key step in myelin regeneration.

What does this mean for patients?

patients
Image: Veronique Miron, Centre for Regenerative Medicine

The results in this study suggest that studying M2 macrophages and activin-A might offer exciting new opportunities for the development of regenerative therapies for multiple sclerosis. In combination with a drug to reduce the initial myelin damage, therapies developed from these new findings may support regeneration of the central nervous system and restore lost functions in multiple sclerosis patients. Future work is needed to understand how activin-A affects oligodendrocytes and to determine the likely safety and effectiveness of potential therapies in humans before any clinical trial for multiple sclerosis could take place.

Further information and links

Acknowledgements & Funding

This summary was written by Veronique E. Miron, Ph.D. and edited by Ingrid Heersche and Emma Kemp. Funding from the United Kingdom Multiple Sclerosis Society, Wellcome Trust, and Multiple Sclerosis Society of Canada supported this scientific work and summary.