Targeting abnormal brain cells may be key to treating progressive MS
Study: DARGs may play a crucial role in driving chronic inflammation
Abnormal brain cells, known as disease-associated radial glia or DARGs, may play a key role in driving chronic inflammation in people with progressive forms of multiple sclerosis (MS), a new study shows.
Based on the finding, researchers are now working to better understand the biology of DARGs, with an eye toward one day creating treatments designed to neutralize these disease-driving cells.
“We’re now working to explore the molecular machinery behind DARGs, and test potential treatments. Our goal is to develop therapies that either correct DARG dysfunction or eliminate them entirely,” Alexandra Nicaise, PhD, co-lead author of the study at the University of Cambridge, said in a university news story. “If we’re successful, this could lead to the first truly disease-modifying therapies for progressive MS, offering hope to thousands living with this debilitating condition.”
The study, “Integrated omics reveals disease-associated radial glia-like cells with epigenetically dysregulated interferon response in multiple sclerosis,” was published in Neuron.
MS driven by inflammation in the brain
Most people with MS are initially diagnosed with relapsing-remitting disease, which is marked by relapses where symptoms suddenly worsen, followed by periods of remission where symptoms ease. Over time, the disease may develop into secondary progressive MS (SPMS), which is marked by symptoms that get gradually worse over time, even in the absence of relapse activity.
MS is driven by inflammation in the brain, and the gradual disability worsening that defines SPMS is believed to be specifically due to chronic or smouldering brain inflammation. But the specific types of cells that drive smouldering inflammation in progressive MS have been hard to pin down.
To gain more insight, researchers collected skin cells from three people with SPMS, as well as three people without MS, who served as controls. Through a series of biochemical manipulations, the researchers reprogrammed the skin cells into induced neural stem cells (iNSCs), which are essentially stem cells that can grow into different types of brain cells.
While the researchers changed the cell type, they took care to preserve the cells’ epigenetic markings — that is, the changes in DNA markers unique to each individual that control gene activity.
DARG cells hyperresponsive to inflammatory signaling molecule
When the researchers examined the iNSCs, they found that some cells from SPMS patients were taking on an unusual set of characteristics. These cells were termed DARGs because they looked like radial glial cells, which are specialized cells normally present in the developing brain that act as scaffolding to help give the brain its structure.
Healthy radial glial cells are able to grow into other types of brain cells, but the DARGs showed signs of senescence, or cellular aging. And although the DARGs weren’t growing, they were by no means inactive.
Essentially, what we’ve discovered are glial cells that don’t just malfunction – they actively spread damage.
In fact, these unusual cells were hyperresponsive to an inflammatory signaling molecule called interferon. When the cells were exposed to interferon, they would release additional inflammatory signaling molecules to trigger inflammation and senescence in nearby cells.
“Our research has revealed a previously unappreciated cellular mechanism that appears central to the chronic inflammation and neurodegeneration driving the progressive phase of the disease,” said Stefano Pluchino, PhD, joint senior author of the study at Cambridge. “Essentially, what we’ve discovered are glial cells that don’t just malfunction – they actively spread damage. They release inflammatory signals that push nearby brain cells to age prematurely, [fueling] a toxic environment that accelerates neurodegeneration.”
Further supporting the idea that DARGs are involved in smouldering inflammation, analyses of brain tissue from people with progressive MS indicated that DARGs are commonly located in areas that show signs of chronic inflammation.
“Our findings reveal that DARGs constitute a discrete subset of disease-associated cells predominantly localized to lesion niches in the MS brain. Their spatial enrichment — alongside glial activation and tissue damage — suggests a potential role in sustaining chronic inflammation,” the researchers wrote.
They added that these findings “suggest that targeting this cellular axis may provide new avenues for therapeutic intervention aimed at disrupting disease progression in [progressive MS].”
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