Researchers have identified a rare and unusual type of brain cell that appears to drive the chronic inflammation and neurodegeneration characteristic of progressive multiple sclerosis. These cells, which are found in much greater numbers in patients with progressive MS, exhibit a strange mix of developmental reversion and premature aging, creating a toxic environment that damages other brain cells.
The discovery offers a significant new understanding of how progressive MS advances and presents a novel target for potential therapies. Scientists believe that finding a way to repair or remove these dysfunctional cells could lead to the first treatments capable of halting the relentless progression of the disease. Published in the journal Neuron, the findings help solve the long-standing mystery of what sustains inflammation within the brain in this advanced stage of the disease, independent of the immune system attacks more commonly associated with relapsing-remitting MS.
A New Cellular Culprit Identified
The newly implicated cells are known as disease-associated radial glia-like cells, or DARGs. These cells are a form of glial cell, which are broadly responsible for supporting the function of neurons in the brain. Investigators found that DARGs appear six times more frequently in the brains of patients with progressive MS compared to healthy individuals. Their presence establishes a critical link between abnormal cellular development and the neurodegenerative processes seen in the disease.
Ordinarily, radial glia are present during early brain development, acting as scaffolds for migrating neurons. The reappearance of cells with these characteristics in adults with MS is highly unusual. This finding challenges the conventional view that MS is driven solely by the body’s peripheral immune system attacking the brain, suggesting that processes originating within the brain itself are a major contributing factor to the progression of the disease.
The Inflammatory and Aging Paradox
The destructive nature of DARG cells lies in their paradoxical behavior. While reverting to an immature, developmental state, they also show clear signs of premature aging, a state known as senescence. In this altered state, the cells begin to secrete molecules that promote inflammation. These inflammatory signals act on neighboring brain cells, such as microglia and oligodendrocytes, inducing premature aging in them as well.
This action creates a feedback loop of damage. The newly aged nearby cells release their own inflammatory substances, further amplifying the toxic environment and accelerating the destruction of nerve fibers and other essential cells. This cycle of persistent, low-grade inflammation, known as “smoldering” pathology, is a key feature of progressive MS and helps explain why disability often worsens even when the brain lesions visible on MRI scans remain unchanged.
Innovative Research Methods
From Skin Cells to Brain Models
The discovery was made possible through an advanced “disease-in-a-dish” approach. Researchers took skin cells from patients with progressive MS and reprogrammed them into induced pluripotent stem cells (iPSCs). These stem cells were then guided to develop into various types of neural cells, creating a model of the patient’s brain tissue in the laboratory. This technique allowed the scientists to observe the intrinsic behaviors of the brain cells in isolation, free from the influence of external immune cells. It was within these cultures that the unexpected appearance and damaging behavior of the DARG cells were revealed.
Uncovering Glia-Intrinsic Roles
For decades, MS research and treatment have focused primarily on therapies that suppress the body’s overactive immune system. While effective for the relapsing-remitting form of MS, this approach has offered little benefit for the progressive stages of the disease. This study shifts the focus inward, demonstrating that glial cells can intrinsically initiate and sustain disease processes. The iPSC models provided a unique platform to dissect these contributions, showing that even without external immune attack, the brain cells of MS patients can generate fewer of the cells responsible for making myelin—the protective sheath around nerve fibers that is damaged in MS.
Context Within Broader MS Research
This new finding complements other emerging lines of research that look beyond the classic white matter lesions of MS. Other studies have used advanced imaging techniques to reveal widespread activation of immune cells called microglia in the brain’s grey matter, linking this inflammation to brain atrophy and physical disability. That research also pointed to damage in brain regions responsible for memory and emotion, which are often affected in MS patients.
Further investigations have centered on mitochondrial dysfunction—the failure of the cellular “powerhouses”—as a driver of damage to specific, highly active neurons known as Purkinje cells, which are essential for balance and motor coordination. The discovery of DARGs adds a crucial piece to this complex puzzle, identifying a specific cell type that may be orchestrating the chronic inflammation, energy failure, and microglial activation that ultimately lead to irreversible nerve cell loss and disability.
Future Therapeutic Avenues
The identification of DARG cells provides a promising new target for drug development. The findings open up the possibility of creating the first disease-modifying treatments designed specifically for progressive MS. Unlike current therapies that broadly suppress the immune system, future treatments could be engineered to selectively target and either remove the harmful DARG cells or find a way to repair them and halt their inflammatory signaling.
Researchers are optimistic that this breakthrough marks a major step toward slowing or even stopping the disease’s progression. By neutralizing the key instigators of chronic inflammation within the brain, it may be possible to protect vulnerable neurons from further damage and preserve function for the millions of people living with progressive MS. The study provides a critical new direction for research aimed at addressing the significant unmet need for effective therapies for this debilitating condition.