Inflammatory brain cells discovered that drive progressive MS

Summary: Researchers have identified a rare type of brain cell that may drive the chronic inflammation and neurodegeneration seen in progressive multiple sclerosis (MS). These cells, called disease-associated radial glia-like cells (DARG), appear six times more often in patients with progressive MS than in healthy individuals.

DARGs return to an early developmental state but also show premature aging, releasing inflammatory signals that accelerate brain cell damage. The discovery could pave the way for targeted treatments that repair or eliminate these dysfunctional cells, marking an important step toward halting the progression of the disease.

Key facts:

Newly identified cell type: DARGs are radial glia-like cells found in large numbers in progressive MS, linking abnormal development to neurodegeneration. Inflammatory function: These cells release immune signals that induce premature aging in nearby brain cells, worsening inflammation and damage. Therapeutic potential: Targeting or eliminating DARGs could lead to the first disease-modifying treatments for progressive MS.

Source: University of Cambridge

Scientists have identified an unusual type of brain cell that may play a vital role in progressive multiple sclerosis (MS), and likely contributes to the persistent inflammation characteristic of the disease.

The discovery, published today in Neuron, is an important step toward 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 people initially experience relapses and remissions, a significant proportion progress 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 from the University of Cambridge, UK, and the National Institute on Aging, US, took skin cells from patients with progressive MS and reprogrammed them into induced neural stem cells (iNSCs), a type of immature 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 cultured brain cells were somehow reverting to an earlier stage of development, transforming into an unusual cell type known as radial glia-like (RG-type) 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 (DARG)-like cells.

These DARGs exhibit characteristic features of radial glia: specialized cells that serve as a scaffold during brain development and possess the ability to differentiate into various types of neural cells.

Essentially, they function as structural support and fundamental building blocks, making them essential for proper brain development. Unexpectedly, DARGs not only revert to an “infantile” state, but also show distinctive 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 “alarm signals” of the immune system, which may help explain the high levels of inflammation seen in MS.

Professor Stefano Pluchino from the Department of Clinical Neurosciences at the University of Cambridge, joint lead 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 critical to the chronic inflammation and neurodegeneration that drive the progressive phase of the disease.

“Basically, what we have discovered are glial cells that not only malfunction, but actively propagate damage. They release inflammatory signals that push nearby brain cells to age prematurely, feeding a toxic environment that accelerates neurodegeneration.”

The team validated their findings by comparing them with human data from people with progressive MS. By analyzing gene expression patterns at the single-cell level, including new data exploring the spatial context of RNA within post-mortem MS brain tissue, they confirmed that DARGs are specifically localized within chronically active lesions, the brain regions that suffer the most significant damage.

Importantly, DARGs were found close to inflammatory immune cells, supporting their role in orchestrating the damaging inflammatory environment characteristic of progressive MS.

By isolating and studying these disease-causing cells in vitro, researchers aim to explore their complex interactions with other types of brain cells, such as neurons and immune cells. This approach will help explain the cellular interference that contributes to disease progression in progressive MS, providing deeper insights into the underlying pathogenic mechanisms.

Dr Alexandra Nicaise, co-lead author of the study from the Department of Clinical Neurosciences at Cambridge, added: “We are now working to explore the molecular machinery behind DARGs and test potential treatments. Our goal is to develop therapies that correct DARG dysfunction or eliminate them completely.”

“If we are successful, this could lead to the first truly disease-modifying therapies for progressive MS, offering hope to thousands of people living with this debilitating condition.”

To date, DARGs have only been observed in a handful of diseases, such as glioblastoma and brain cavernomas, groups of abnormal blood vessels. However, this may be because until now scientists have lacked the tools to find them.

Professor Pluchino and his colleagues believe their approach is likely to reveal that DARGs play an important role in other forms of neurodegeneration.

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

Key questions answered:

About these research developments in neurology and multiple sclerosis

Author: Craig Brierley
Source: University of Cambridge
Contact: Craig Brierley – University of Cambridge
Image: Image is credited to Neuroscience News.

Original research: Open access.
“Integrated multiomics reveals disease-associated radial glia-like cells with epigenetically dysregulated response to interferon in progressive multiple sclerosis” by Stefano Pluchino et al. Neuron

Abstract

Integrated multiomics reveals disease-associated radial glia-like cells with epigenetically dysregulated response to interferon in progressive multiple sclerosis

Progressive multiple sclerosis (PMS) involves a persistent and maladaptive inflammatory process with numerous cellular drivers.

We generated induced neural stem cells (iNSCs) from patient fibroblasts through a direct reprogramming protocol that preserved their epigenome, revealing PMS-specific hypomethylation of lipid metabolism and interferon (IFN) signaling genes.

Single-cell multiomics uncovered a novel subpopulation of disease-associated radial glia-like (DARG) cells in PMS cell lines that exhibit senescence and potent IFN responsiveness driven by specific transcription factors.

Functionally, PMS iNSCs induced paracrine senescence and inflammation in control cells, which were inhibited by senolytic treatment.

We identified in PMS brains a distinct population of senescent, IFN-responsive DARGs that were developmentally aligned with the trajectories of iNSCs in vitro and spatially associated with inflammatory glia in chronically active lesions.

DARGs may maintain latent inflammation, revealing a previously unrecognized cellular axis that could underpin the mechanisms of neurodegeneration.

This discovery offers novel insights into disease mechanisms and highlights potential therapeutic targets.