Scientists have discovered an uncommon type of brain cell that may be central to the relentless inflammation seen in progressive multiple sclerosis (MS).
This finding, published today in Neuron, represents a major step toward decoding the intricate pathways that fuel MS and offers a fresh direction for developing more effective treatments.
MS is a long‑term disease in which the immune system mistakenly attacks the brain and spinal cord, breaking the communication link between the brain and the rest of the body. While many patients first experience flare‑ups and remissions, a large proportion move into a progressive stage marked by continuous neurological decline and few therapeutic options.
To mimic the disease in a controlled setting, researchers at the University of Cambridge, UK, and the National Institute on Aging, US, collected skin cells from patients with progressive MS and re‑programmed them into induced neural stem cells (iNSCs). These immature cells can divide and transform into a variety of brain cell types.
Using this “disease in a dish” strategy, the team observed that a subset of the derived brain cells appeared to revert to an earlier developmental state, becoming a distinctive class of radial glia‑like (RG‑like) cells. Remarkably, these cells were about six times more frequent in iNSC lines from progressive MS patients than in those from healthy controls, and were therefore named disease‑associated RG‑like cells (DARGs).
These DARGs share the key attributes of radial glia—cells that act as scaffolds during brain formation and can generate many different neural types. Consequently, they provide both structural support and essential building blocks for normal brain development. Unexpectedly, DARGs not only return to an infantile state but also display features of cellular aging (senescence).
The newly identified DARGs show a distinct epigenetic signature—chemical markings that regulate gene activity—though the drivers of this pattern remain to be clarified. These changes amplify the cells’ response to interferons, the immune system’s alarm signals, possibly explaining the heightened inflammation characteristic of MS.
Professor Stefano Pluchino of the University of Cambridge’s Department of Clinical Neurosciences, a joint senior author, explained, “Progressive MS is devastating, and effective treatments are scarce. Our work reveals a previously unrecognized cellular mechanism that seems integral to the chronic inflammation and neurodegeneration that propel the disease’s progressive stage.
In essence, we have uncovered glial cells that do more than malfunction—they actively spread harm. They release inflammatory cues that push neighboring brain cells toward premature aging, creating a toxic environment that accelerates neurodegeneration.”
The team corroborated their results by comparing them with human data from progressive MS patients. Single‑cell gene‑expression mapping—including new spatial RNA analyses of post‑mortem MS brain tissue—confirmed that DARGs are specifically located within chronically active lesions, where the most severe damage occurs. Importantly, DARGs were found adjacent to inflammatory immune cells, supporting their role in orchestrating the damaging inflammatory milieu of progressive MS.
By isolating these disease‑propelling cells in vitro, researchers aim to dissect their complex interactions with other brain cell types, such as neurons and immune cells. This work will illuminate the cellular crosstalk that fuels disease progression in progressive MS, deepening our understanding of pathogenic mechanisms.
Dr. Alexandra Nicaise, co‑lead author from the University of Cambridge’s Department of Clinical Neurosciences, added, “We are now working to untangle the molecular machinery of DARGs and to test potential therapies. Our objective is to develop treatments that either correct DARG dysfunction or remove them entirely.”
“If successful, this could herald the first genuine disease‑modifying therapies for progressive MS, offering hope to thousands affected by this debilitating condition.”
To date, DARGs have only been detected in a few conditions, such as glioblastoma and cerebral cavernomas—clusters of abnormal blood vessels. However, this likely reflects a lack of sensitive detection tools. Professor Pluchino and colleagues believe their approach will uncover a broader role for DARGs in other neurodegenerative disorders.