byIngrid Fadelli, Medical Xpress

Stormy weather: oligodendrocyte dynamics in a mouse model of multiple sclerosis. Castelo-Branco research group, Karolinska Institutet. Credit: Bastien Hervé and Lilian Hervé (Instagram, @tibali_).

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by the disruption of nerve signals and various associated neurological symptoms, ranging from vision problems to numbness, weakness, fatigue and cognitive impairments. These symptoms emerge when the immune system starts to attack mature oligodendrocytes (MOLs), specialized cells that produce the protective sheath surrounding nerve fibers (i.e., myelin).

There are several subtypes of MOLs, which might exhibit different immune cell-like genetic responses in patients diagnosed with MS. While various studies have investigated the neural and molecular underpinnings of MS, how these different cell subtypes respond as the disease progresses has not yet been elucidated.

Researchers at Karolinska Institute in Sweden recently carried out a mouse study aimed at mapping how different MOL subtypes might differ in their sensitivity to neuroinflammation across different stages of MS.

Their findings,publishedinNature Neuroscience, could inform future research focusing on the underpinnings of MS, potentially informing the development of new therapeutic strategies.

"We had previously found that oligodendroglia (composed of different types of MOLs and their progenitors), usually thought to be a passive target in MS, can transition to disease-associated states at the peak of disease in a mouse model of MS," Gonçalo Castelo-Branco, senior author of the paper, told Medical Xpress.

"We wanted to understand when this state arose and if it was persistent in later stages of the disease."

Rather than studying MOLs in humans, Castelo-Branco and his colleagues looked at their responses in mice that exhibit myelin degradation and nerve signal disruptions that resemble some aspects of MS in human patients. These mice are affected by a condition known as encephalomyelitis (EAE), which is also characterized by immune responses targeting MOLs.

"We followed oligodendroglia throughout key time points during the development of the disease in this mouse model, analyzing these cells at an individual level, and examining at the same time which genes were active and how their activity was regulated at a chromatin level, using a technology calledsingle cell multiomics," explained Castelo-Branco.

The researchers used a technique known as single-cell multiome profiling to examine the accessibility of DNA and the expression of RNA in individual cells in the mice's nervous system as the MOL-targeting immune disease progressed.

They also identified different types ofMOL subtypesand tracked changes in each of these types of cells' gene activity at different stages of the condition.

Castelo-Branco and his colleagues observed that immune-like states affecting MOLs appeared when the mice were at early stages of the MS-like disease and continued until the most advanced stages. Yet they also found that different MOL subtypes responded differently at different stages of the disease, with some exhibiting strong immune responses and others weakly.

"We observed that different subtypes of MOLs react differently to the disease environment, where one oligodendrocyte population is more prone to transition to animmune-like state, while another oligodendrocyte population is possibly more amenable to regenerative processes," said Castelo-Branco.

"Their findings also suggest that these cells, at late stages of the disease, might still retain anepigenetic memoryof earlier inflammatory environments."

If validated in humans diagnosed with MS, the results of this recent study could offer new insight into the disease's molecular underpinnings and how it impacts different types of MOLs.

In the future, the team's efforts might also inform the development of new promising treatments for MS that target specific MOL subtypes.

"We are now exploring these molecular and temporal dynamics in MS patient tissues and also using technologies that allow us to analyze these dynamics at a spatial level in these tissues," added Castelo-Branco.

"This would allow us to understand how different cell populations interact with each other in the context of the disease."

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More information Chao Zheng et al, Distinct transcriptomic and epigenomic responses of mature oligodendrocytes during disease progression in a mouse model of multiple sclerosis, Nature Neuroscience (2025). DOI: 10.1038/s41593-025-02100-3 . Journal information: Nature Neuroscience