Summary: Researchers have identified a rare brain cell type that appears to drive chronic inflammation and neurodegeneration in progressive multiple sclerosis (MS). These cells, termed disease-associated radial glia-like (DARG) cells, occur about six times more often in cells derived from people with progressive MS than in controls.
DARGs revert to an early developmental, radial glia-like state while simultaneously showing signs of premature cellular aging and a heightened inflammatory profile. They secrete immune signals that can force neighboring brain cells into senescence, creating a toxic environment that accelerates neuronal damage. This discovery opens a promising path for therapies that either repair or remove these dysfunctional cells to slow or stop progression in progressive MS.
Key Facts:
- Newly identified cell type: DARGs are radial glia–like cells found at much higher frequency in progressive MS samples, linking developmental programs with neurodegeneration.
- Inflammatory and senescent behavior: DARGs show an exaggerated interferon response and paracrine effects that induce premature aging in nearby cells, sustaining chronic inflammation.
- Therapeutic potential: Targeting the pathways that create or maintain DARGs, or selectively removing these cells, could yield the first disease-modifying strategies for progressive MS.
Source: University of Cambridge
Overview
Scientists from the University of Cambridge (UK) and the National Institute on Aging (US) have described a previously unrecognized cellular population that may be central to progressive multiple sclerosis. Published in Neuron, the study combines patient-derived cell models and human tissue analyses to reveal how a small subset of cells may perpetuate the harmful inflammation that underlies progressive MS.
Multiple sclerosis is an immune-mediated disorder in which the nervous system is attacked, impairing the brain’s communication with the body. Many patients experience relapsing phases early in the disease, but a significant number progress to a steady decline in neurological function—progressive MS—a stage with limited treatment options and ongoing, smoldering inflammation.
To model disease mechanisms, the research team reprogrammed skin cells from people with progressive MS into induced neural stem cells (iNSCs). This “disease-in-a-dish” strategy preserved key epigenetic marks and allowed investigators to observe disease-relevant cellular behaviors that are difficult to detect in bulk tissue.
Within these cultures, a distinct subpopulation of cells reverted to a radial glia-like developmental state. These cells were highly enriched in lines derived from progressive MS patients—about sixfold greater than in controls—and were therefore named disease-associated radial glia-like cells (DARGs).
DARGs display features of radial glia, the neural scaffolding and progenitor cells essential during brain development. Unexpectedly, DARGs combine this immature identity with molecular and functional signatures of cellular senescence. Their epigenetic profile shows hypomethylation at genes involved in lipid metabolism and interferon signaling, producing an exaggerated response to interferon-type immune signals.
Functionally, conditioned media from progressive MS iNSCs induced inflammation and paracrine senescence in control cells, effects that were reduced by senolytic treatments. These data indicate that DARGs actively drive a damaging, self-sustaining inflammatory niche rather than being passive bystanders.
The team validated these in vitro findings using human post-mortem tissue. Single-cell and spatial gene-expression analyses revealed that DARG-like cells are present in progressive MS brains and are concentrated in chronically active lesions—the areas showing the most persistent damage. There, DARGs reside near inflammatory immune cells, consistent with a role in orchestrating local inflammation and neurodegeneration.
Co-lead author Dr Alexandra Nicaise and joint senior author Professor Stefano Pluchino emphasize that understanding the molecular machinery behind DARG formation and persistence is now a priority. By interrogating DARG-specific transcriptional and epigenetic drivers, researchers aim to identify interventions that either correct DARG dysfunction or selectively eliminate these disease-promoting cells.
Although DARG-like cells have previously been reported in a few other brain conditions—such as glioblastoma and cerebral cavernomas—the new study suggests that the scarcity of reports may reflect limited detection tools rather than true rarity. The authors propose that DARGs may be a broader pathogenic element across multiple forms of neurodegeneration.
Funding: This work was supported by the Medical Research Council, the Wellcome Trust, the National MS Society, FISM – Fondazione Italiana Sclerosi Multipla, 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, and the Ferblanc Foundation.
Key Questions Answered
A: DARGs (disease-associated radial glia-like cells) are immature, inflammation-promoting brain cells that re-emerge and adopt premature aging features in progressive multiple sclerosis.
A: They may explain the persistence of chronic inflammation in progressive MS and represent novel targets for interventions designed to slow or reverse tissue damage.
A: Researchers reprogrammed patient skin cells into induced neural stem cells and used single-cell multi-omics and spatial transcriptomics to detect and validate the presence and behavior of DARGs in progressive MS.
About this neurology and multiple sclerosis research news
Author: Craig Brierley
Source: University of Cambridge
Contact: Craig Brierley – University of Cambridge
Image: The image is credited to Neuroscience News
Original Research: Open access. Title: “Integrated Multi-Omics Reveals Disease-Associated Radial Glia-like Cells with Epigenetically Dysregulated Interferon Response in Progressive Multiple Sclerosis” by Stefano Pluchino et al., published in Neuron.
Abstract
Integrated Multi-Omics Reveals Disease-Associated Radial Glia-like Cells with Epigenetically Dysregulated Interferon Response in Progressive Multiple Sclerosis
Progressive multiple sclerosis (PMS) is driven by persistent maladaptive inflammation with multiple cellular contributors. By directly reprogramming patient fibroblasts into induced neural stem cells (iNSCs) while preserving epigenetic marks, researchers identified PMS-specific hypomethylation of lipid metabolism and interferon signaling genes. Single-cell multi-omics uncovered a novel DARG subpopulation in PMS iNSC lines that combined senescence with potent interferon responsiveness driven by distinct transcription factors. Functionally, PMS iNSCs caused paracrine senescence and inflammation in control cells, effects that could be mitigated with senolytic treatment. In post-mortem PMS brains, a matching population of senescent, interferon-responsive DARGs aligned with in vitro developmental trajectories and localized to chronically active lesions near inflammatory glia. These findings suggest DARGs sustain smoldering inflammation and reveal a previously unrecognized cellular axis underlying neurodegeneration, highlighting new potential therapeutic targets.