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

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, and National Institute on Aging, in the U.S., took skin cells from patients with progressive MS and reprogrammed them into induced neural stem cells, 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 cells.

Notably, these cells were highly specific and appeared approximately six times more frequently in induced neural stem cells lines derived from individuals with progressive MS compared to controls. As a result, they were designated as disease-associated radial glia-like cells.

These disease-associated radial glia-like cells 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 fundamental building blocks, making them critical for proper brain development. Unexpectedly, disease-associated radial glia-like cells not only revert to an ‘infant’ state but also display hallmark features of premature aging, or senescence.

These newly identified disease-associated radial glia-like cells 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.

The team validated their findings by cross-referencing with human data from individuals with progressive MS. By analysing 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 disease-associated radial glia-like cells are specifically localized within chronically active lesions, the regions of the brain that sustain the most significant damage.

Importantly, disease-associated radial glia-like cells were found near inflammatory immune cells, supporting their role in orchestrating the damaging inflammatory environment characteristic of progressive MS.

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

The researchers said they are now working to explore the molecular machinery behind disease-associated radial glia-like cells, and test potential treatments. The goal is to develop therapies that either correct disease-associated radial glia-like cell dysfunction or eliminate them entirely. If successful, it could lead to the first truly disease-modifying therapies for progressive MS, offering hope to thousands living with this debilitating condition.

The findings were published in the journal Neuron.