Summary: Injecting the brain molecule into mouse models of multiple sclerosis increased the number of oligodendrocytes. The findings suggest fractalkine may help to slow the progression, or potentially halt multiple sclerosis.
Source: University of Alberta
A University of Alberta researcher is one step closer to demonstrating the potential of a brain molecule called fractalkine to halt and even reverse the effects of multiple sclerosis and other neurodegenerative diseases.
Multiple sclerosis is an autoimmune disease in which the myelin, or fatty lining of nerve cells, is eroded, leading to nerve damage and slower signaling between the brain and the body. MS symptoms range from blurred vision to complete paralysis, and while there are treatments, the causes are not fully understood and nothing exists to reverse the disease process. More than 90,000 Canadians live with MS, according to the MS Society.
In new research published in Stem Cell Reports, Anastassia Voronova, assistant professor in the Faculty of Medicine & Dentistry and Canada Research Chair in Neural Stem Cell Biology, injected fractalkine into mice with chemically induced MS.
She found the treatment increased the number of new oligodendrocytes—vital brain and spinal cord cells that produce myelin in both embryonic and adult brains—which are damaged during the MS autoimmune attack.
“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 says. “That’s the Holy Grail in the research community and something that we’re very passionate about.”
Hoping to meet an unmet need
Voronova’s earlier research tested the safety and efficacy of fractalkine in normal mice and found similar beneficial effects. Other researchers have demonstrated that fractalkine may provide protection for nerves in mouse models before the disease is induced, but this is the first time it has been tested on animals that already have the disease.
“What was important to us is to approximate it to the clinic,” Voronova points out. “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.”
Voronova and her team observed new oligodendrocytes, as well as reactivated progenitor cells that can regenerate oligodendrocytes, in the brains of the treated animals. Remyelination occurred in both the white and gray matter. The researchers also observed a reduction in inflammation, part of the damage caused by the immune system.
Next steps for the treatment include testing it in other diseased mouse models, including those with neurodegenerative diseases other than MS. Voronova is working with colleagues at the U of A to search for ways to easily deliver fractalkine to the brain, such as through a nasal spray.
Voronova is a developmental and stem cell biologist by training, so she also hopes to test and develop other brain molecules that she originally discovered while doing basic research on the embryonic brain.
“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 central nervous system,” Voronova says.
Fractalkine enhances oligodendrocyte regeneration and remyelination in a demyelination mouse model
CX3CR1 is expressed in mouse and human microglia and OPCs in demyelinated brain
Intracerebral fractalkine infusion after demyelinating injury enhances remyelination
Fractalkine enhances oligodendrogenesis by directly regulating microglia and OPCs
Demyelinating disorders of the central nervous system (CNS) occur when myelin and oligodendrocytes are damaged or lost. Remyelination and regeneration of oligodendrocytes can be achieved from endogenous oligodendrocyte precursor cells (OPCs) that reside in the adult CNS tissue.
Using a cuprizone mouse model of demyelination, we show that infusion of fractalkine (CX3CL1) into the demyelinated murine brain increases de novo oligodendrocyte formation and enhances remyelination in the corpus callosum and cortical gray matter.
This is achieved by increased OPC proliferation in the cortical gray matter as well as OPC differentiation and attenuation of microglia/macrophage activation both in corpus callosum and cortical gray matter.
Finally, we show that activated OPCs and microglia/macrophages express fractalkine receptor CX3CR1 in vivo, and that in OPC-microglia co-cultures fractalkine increases in vitro oligodendrocyte differentiation by modulating both OPC and microglia biology.
Our results demonstrate a novel pro-regenerative role of fractalkine in a demyelinating mouse model.