By shedding light on how cells regenerate the myelin sheath surrounding nerve fibres in the brain, a new study published in Nature Neuroscience opens the door to treatments that could repair nerve damage and restore lost function in patients with multiple sclerosis (MS).
MS is a disease in which the immune system attacks and destroys myelin, the protein that insulates the nerves in the spinal cord, brain and optic nerve and stops the electrical signals from leaking out.
As the myelin is gradually destroyed, patients experience symptoms ranging from mild numbness in the limbs to paralysis or blindness.
The disease progresses not just because the immune system gradually destroys the myelin, but also because a natural repair process fails. Cells called oligodendrocytes are able to repair the myelin damage themselves – “remyelination” – but in MS this fails after a while.
There are over 400,000 living with MS in the European Union. There are currently no approved therapies that tackle the disease by promoting regeneration of the myelin.
In this latest study, led by the Universities of Edinburgh and Cambridge in the UK, researchers describe how they studied immune cells called macrophages, known to be involved in remyelination, and found two important features that could lead to new therapies that promote myelin regeneration:
- For remyelination to proceed, macrophages have to become anti-inflammatory
- Macrophages release a protein called activin-A that actively encourages remyelination.
First author Dr Veronique Miron, of the Medical Council Centre for Regenerative Medicine at the University of Edinburgh, says in a statement:
“Approved therapies for multiple sclerosis work by reducing the initial myelin injury – they do not promote myelin regeneration.
This study could help find new drug targets to enhance myelin regeneration and help to restore lost function in patients with multiple sclerosis.”
For their study, Miron and colleagues examined myelin regeneration in human tissue samples and in mice.
They wanted to understand what stimulates remyelination and which biological molecules, cells, or other factors may be involved that could serve as targets for regenerative treatments that restore lost vision, movement and other functions in people with MS.
Previous studies have shown that macrophages – immune cells that gobble up disease pathogens, debris and other undesirable materials, among other things – are also involved in regeneration.
For example, there is a group of macrophages called M2 that is essential for regenerating skin and muscle.
So what Miron and the team wanted to find out was whether M2 macrophages were also involved in myelin regeneration, and if so, were there particular molecules involved in stimulating remyelination that could serve as useful drug targets?
On examining a mouse model of human myelin damage and regeneration, the team found that M2 macrophages were present and increased in number when remyelination started. This suggests, they say, that M2 macrophages may control remyelination.
Previous research had already established that oligodendrocytes are the cells that normally produce the myelin found in the brain and spinal cord, so Miron and colleagues set about trying to discover if M2 macrophages were able to trigger the oligodendrocytes on their own, or whether they needed to work with another group of cells or processes.
To find out they put some oligodendrocytes in a test tube and exposed them to proteins released by M2 macrophages.
The result was a success. Exposure to M2 macrophage proteins spurred the oligodendrocytes to make more myelin.
The researchers also found that when they took M2 macrophages out of the equation, remyelination dramatically reduced, showing they were necessary for myelin to regenerate.
This was confirmed in further examinations of mouse models of remyelination, and brain tissue from people with MS. The researchers found in both cases that high numbers of M2 macrophages are present when remyelination is efficient, and the numbers are vastly reduced when it is not.
The team also found that a protein produced by macrophages, activin-A, contributes to the regenerative effects of M2 macrophages.
They found high levels of activin-A in M2 macrophages when remyelination was starting and also when they added the protein to oligodendrocytes in test tubes they started to make myelin.
To confirm the role of activin-A, the researchers blocked its effect on oligodendrocytes after myelin damage, and discovered the M2 macrophages were not as able to stimulate them to make more myelin.
They conclude that their findings point to a key step in myelin regenration, namely that when M2 macrophages release activin-A, they spur oligodendrocytes to make myelin.
The study suggests it may be possible to partner drugs that reduce the initial myelin damage, with ones that regenerate it in the central nervous system and thus restore lost functions in MS patients.
The researchers now plan to look in more detail at how activin-A works and whether its effects can be enhanced.
The study was funded by the MS Society, the Wellcome Trust and the Multiple Sclerosis Society of Canada.
In another study published earlier this year, researchers described how a new treatment for MS that resets the patient’s immune system was found to be safe and well tolerated in a small trial.