Fractalkine Found to Promote Remyelination in MS Mouse Model
Protein may be novel candidate for slowing or halting disease progression
The signaling protein fractalkine was found to promote the repair of myelin — the protecting coating around nerve fibers — that is damaged by the mistaken immune attack that leads to multiple sclerosis (MS), a mouse study demonstrated.
In an animal model of the disease, the molecule triggered both the growth of new myelin-producing cells and the reduction of pro-inflammatory immune cells in the brain. This led to a more effective regeneration of lost myelin, known as remyelination.
Given these findings, fractalkine may be a novel therapeutic candidate for reversing myelin damage and potentially slowing or halting MS progression, the researchers noted.
“We’ve made a lot of progress in the medical and research communities on disease-modifying therapies for multiple sclerosis, but what we really don’t have — and is an unmet need in the multiple sclerosis community — is regenerative therapies for the [brain and spinal cord],” Anastassia Voronova, PhD, an assistant professor at the University of Alberta, in Canada, and the study’s lead author, said in a university press release.
The study, “Fractalkine enhances oligodendrocyte regeneration and remyelination in a demyelination mouse model,” was published in the journal Stem Cell Reports.
Fractalkine shows promise in MS mouse model
In MS, a self-directed immune attack damages myelin and the cells, called oligodendrocytes, that produce myelin. Myelin can be restored by stimulating oligodendrocyte precursor cells (OPCs) to become new oligodendrocytes. In MS patients, however, this process is highly inefficient.
“If we can replace those lost or damaged oligodendrocytes, then they could make new myelin and it is believed that would halt the disease progression, or maybe even reverse some of the symptoms,” Voronova said.
“That’s the Holy Grail in the research community and something that we’re very passionate about,” she added.
A team led by Voronova previously discovered that fractalkine helped stimulate OPCs to grow into mature oligodendrocytes more quickly. Other animal studies supported these findings by showing that fractalkine may protect nerve fibers before disease onset.
Now, Voronova’s team tested the impact of fractalkine in a mouse model with established MS disease.
“What was important to us is to approximate it to the clinic,” Voronova said. “When a person with MS is diagnosed, the injury has already occurred, there’s some kind of attack that has already happened on the oligodendrocytes and myelin.”
If we can replace … lost or damaged oligodendrocytes, then they could make new myelin and it is believed that would halt the disease progression, or maybe even reverse some of the symptoms.
To create the MS mouse model, healthy mice were fed a six-week diet containing cuprizone, a chemical that triggers myelin loss. The MS mice then were infused with fractalkine directly into the brain for three days. Following the treatment, the mice were returned to a regular diet so as to allow new myelin formation.
With fractalkine, OPCs and mature oligodendrocytes increased up to twofold in the brains of MS mice compared with untreated control mice. This demonstrated that “[fractalkine] infusion leads to a persistent increase in the number of [new] oligodendrocytes from activated [OPCs],” the researchers wrote.
Fractalkine treatment also reduced the proportion and number of pro-inflammatory microglia, a type of immune cell that patrols the brain and spinal cord and is thought to contribute to MS. In contrast, fractalkine did not attenuate the activation of astrocytes, supportive star-shaped brain cells that also play a role in MS-related nerve damage.
Fractalkine found to increase myelin density
An analysis of brain tissue showed that fractalkine significantly increased myelin density, indicating enhanced remyelination, with a trending increase in the proportion of total myelinated nerve fibers.
At the same time, there was a significant increase in the density and proportion of both small and medium-diameter nerve fibers, with no changes in the large-diameter fibers. Further experiments demonstrated that fractalkine remyelinated both white and grey matter — brain regions made mostly of nerve fibers and nerve cell bodies, respectively.
To understand how fractalkine modulates OPCs, the team cultured these cells and microglia, alone and together. Fractalkine was found to directly, but only partially, enhance OPC stimulation.
The researchers noted that the proportion of mature oligodendrocytes only increased when fractalkine-treated OPCs and microglia were grown together. These findings “demonstrate that [fractalkine] acts on both OPCs and microglia to increase oligodendrocyte formation,” the team wrote.
Consistent with the mouse experiments, treating only microglia with fractalkine suppressed their pro-inflammatory features. This process was facilitated by the fractalkine-stimulated increased production of Cx3cr1, the protein receptor for fractalkine.
Finally, fractalkine directed microglia to ingest and clear myelin debris caused by nerve damage, which clears the way for new myelin formation.
“We demonstrate that infusion of [fractalkine] into the brain after demyelinating injury increases oligodendrocyte and myelin regeneration from [OPCs],” the researchers concluded. “Therefore, [fractalkine] represents a novel candidate for remyelination strategies.”
According to Voronova, fractalkine will be tested in other mouse models, including those with neurodegenerative diseases other than MS. In collaboration with colleagues at the university, the researcher aims to find a convenient way to deliver fractalkine to the brain, such as via a nasal spray.
This research was backed by the MS Society of Canada, the Canadian Institutes of Health Research, and Canada Research Chair funds. Additional support came from the U.K. MS Society Grant, the Natural Sciences and Engineering Research Council of Canada, and the Canadian Glycomics Network.
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