Multiple sclerosis (MS) is an autoimmune condition in which the protective insulation surrounding neurons in the brain and spinal cord is erroneously attacked. This can cause a wide variety of serious problems, like fatigue, dizziness, tremors, cognitive difficulties, and vision changes. There are many suspected causes of MS, including parasitic infections, Epstein-Barr virus (EBV) infections in people with a genetic susceptibility, and vitamin D deficiency. Now, scientists have found a specific type of brain cell that is closely connected to MS, and may be related to the chronic inflammation that is a hallmark of the disease. The findings, which could eventually help scientists develop better MS treatments, have been reported in Neuron.
In this study, researchers obtained skin cells from MS patients in advanced stages of disease. The skin cells were reprogrammed to create a cell type that would be able to divide and differentiate into several different kinds of brain cells. But the researchers found that some of these reprogrammed cells were becoming a special type of cell called radial glia-like (RG-like) cells. This phenomenon was six times more likely in the reprogrammed cells, or induced neural stem cells (iNSCs), from MS patients than unaffected individuals.
The researchers named these cells disease-associated RG-like cells (DARGs). These cells were found to be similar to radial glia, which act as scaffolds in brain development that can differentiate into multiple types of neurons. These radial glia cells work like building blocks and are crucial to the development of the brain. But DARGs are abnormal, and often stop dividing, entering a state known as senescence.
This study showed that DARGs carry unusual epigenetic patterns, which can affect gene expression. The scientists have not yet determined what causes these epigenetic changes. However, they seem to be boosting the response to immune signaling molecules known as interferons. This could help explain why inflammation levels are so high in MS patients.
“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 co-corresponding study author Professor Stefano Pluchino of the University of 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.”
The investigators also confirmed these results by assessing gene expression data from MS patients. Wirth single-cell sequencing data, they determined that DARGs can be found in areas of the brain that have sustained significant, MS-related damage–chronically active lesions. DARGs were also located close to inflammatory immune cells, showing that they could be helping to create the chronic inflammation observed in progressive MS.
"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,” noted co-corresponding study author Dr. Alexandra Nicaise, also of the University of Cambridge. "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."
Sources: University of Cambridge, Neuron
