‘Disease in a dish’ study of progressive MS finds critical role for unusual type of brain cell

20. 10. 2025

Scientists have identified an unusual type of brain cell that may play a vital role in progressive multiple sclerosis (MS), likely contributing to the persistent inflammation characteristic of the disease. The discovery, reported last week in Neuron, is a significant step towards understanding the complex mechanisms that drive the disease and provides a promising new avenue for research into more effective therapies for this debilitating condition.

MS is a chronic disease in which the immune system mistakenly attacks the brain and spinal cord, disrupting communication between the brain and the body. While many individuals initially experience relapses and remissions, a significant proportion transition to progressive MS, a phase marked by a steady decline in neurological function with limited treatment options. To model what is happening in the disease, researchers at the University of Cambridge, UK, and National Institute on Aging, US, took skin cells from patients with progressive MS and reprogrammed them into induced neural stem cells (iNSCs), an immature type of cell capable of dividing and differentiating into various types of brain cells. Using this ‘disease in a dish’ approach, the team observed that a subset of the cultured brain cells was somehow reverting to an earlier developmental stage, transforming into an unusual cell type known as radial glia-like (RG-like) cells. Notably, these cells were highly specific and appeared approximately six times more frequently in iNSC lines derived from individuals with progressive MS compared to controls. As a result, they were designated as disease-associated RG-like cells (DARGs).

These DARGs exhibit characteristic features of radial glia—specialized cells that serve as scaffolding during brain development and possess the capacity to differentiate into various neural cell types. Essentially, they function both as structural support and as fundamental building blocks, making them critical for proper brain development. Unexpectedly, DARGs not only revert to an ‘infant’ state but also display hallmark features of premature aging, or senescence. These newly identified DARGs possess a distinctive epigenetic profile—patterns of chemical modifications that regulate gene activity—although the factors influencing this epigenetic landscape remain unclear. These modifications contribute to an exaggerated response to interferons, the immune system’s ‘alarm signals,’ which may help explain the high levels of inflammation observed in MS.

Professor Stefano Pluchino from the Department of Clinical Neurosciences at the University of Cambridge, joint senior author, said: “Progressive MS is a truly devastating condition, and effective treatments remain elusive. 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. 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, fuelling a toxic environment that accelerates neurodegeneration.”

To confirm these findings in the human brain, the team collaborated with researchers at the Institute of Biotechnology of the Czech Academy of Sciences. The Czech team, represented by Dr. Lukas Valihrach and senior bioinformatician Daniel Zucha, performed a large-scale re-analysis of three publicly available spatial transcriptomics datasets from post-mortem human brain tissue, encompassing over 200 tissue sections from 31 MS patients and 12 controls. This advanced technique, which maps gene activity within the physical structure of the tissue, revealed that DARGs are not randomly scattered but are significantly enriched in the most damaged areas of the brain in MS patients, particularly at the edges of chronic active lesions.

Dr. Lukas Valihrach, a senior author on the study from the Institute of Biotechnology of the Czech Academy of Sciences, commented: “Finding these unique cells in ‘a dish’ was a breakthrough, but the critical next step was to see if they exist and where they are in the actual brains of patients. Spatial transcriptomics gives us a map, showing not just what cells are present, but how they are organized and interacting within the damaged tissue. This work also highlights the incredible value of open science. By re-analyzing publicly available datasets, we were able to add a crucial layer of evidence, confirming that these DARGs are concentrated in the very regions where the disease is actively causing damage.” Daniel Zucha, a senior bioinformatician from the same institute, added: “Working with massive spatial transcriptomics datasets requires sophisticated computational approaches. Our analysis allowed us to pinpoint the DARG signature within these complex tissue maps. We found a clear spatial correlation: where DARG levels were high, we also saw more inflammatory glial cells and greater tissue damage. This spatial link strongly suggests they are active players in the disease process, not just passive bystanders.”

Dr Alexandra Nicaise, co-lead author of the study from the Department of Clinical Neurosciences at the University of Cambridge, added: “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. 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.” To date, DARGs have only ever been seen in a handful of diseases to date, such as glioblastoma and cerebral cavernomas, clusters of abnormal blood vessels. However, this may be because scientists have until now lacked the tools to find them. Professor Pluchino and colleagues believe their approach is likely to reveal that DARGs play an important role in other forms of neurodegeneration.

This work received funding from the Medical Research Council, the Wellcome Trust, the National MS Society, FISM - Fondazione Italiana Sclerosi Multipla, the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), the National Institute on Aging, the UK Dementia Research Institute, the Austrian Science Fund FWF, the UK MS Society Centre of Excellence, the Bascule Charitable Trust, the Czech Science Foundation, MULTIOMICS CZ, and the Ferblanc Foundation.

Reference

Park, B. et al. Integrated Multi-Omics Reveals Disease-Associated Radial Glia-like Cells with Epigenetically Dysregulated Interferon Response in Progressive Multiple Sclerosis. Neuron. 2025 Oct 10:S0896-6273(25)00710-X. doi: 10.1016/j.neuron.2025.09.022.

‘Disease in a dish’ study of progressive MS finds critical role for unusual type of brain cell

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