��ѿ��ý

Mapping MS-like lesions in marmosets

Multiple sclerosis is caused by the immune system attacking the protective sheath around nerve cells in the brain. Lightspring / Shutterstock

Nerve cells have a protective covering called myelin that provides electrical insulation needed for them to function. Myelin is produced by oligodendrocytes, one of various types of non-neuronal cells in the brain called glial cells. In MS, the body’s immune system attacks myelin and creates lesions in the brain. The damage can lead to nerve cell death.

Much of our understanding of how MS develops comes from brain tissue collected after death. But these only provide snapshots of the disease, often decades after onset, and can miss details of early development.

A team of researchers, led by Drs. Jing-Ping Lin and Daniel Reich at NIH’s National Institute for Neurological Disorders and Stroke (NINDS), sought to map the early stages of MS lesion formation. To do so, they studied experimental autoimmune encephalitis (EAE), a model of MS, in common marmosets. The team combined MRI imaging data, brain tissue pathology, and gene activity (or expression) to track MS-like lesion changes over time. Their findings appeared in Science on February 28, 2025.

The researchers identified five distinct brain environments that emerged as lesions developed. The cores of MS lesions tended to center around areas bordering blood vessels and the fluid-filled brain ventricles. The first cells to respond were oligodendrocyte precursor cells (OPCs) and immune cells called microglia, both originating in the brain. These gave way to different types of immune cells called monocytes and lymphocytes, which entered the brain from the bloodstream.

During lesion formation, glial cells formed concentric layers around the lesion cores. The innermost layer consisted largely of OPCs. Surrounding this were layers of versatile glia called astrocytes. In particular, astrocytes marked by expression of a gene called SERPINE1 appeared at the start of, or even before, lesion formation. SERPINE1 astrocytes appeared to be central to coordinating other cells’ responses.

The team was also able to identify an MRI signal that could pinpoint where lesions were likely to occur.

The findings suggest that SERPINE1 astrocytes play a key role in lesion formation. Their early response may be part of a protective mechanism that then goes awry and contributes to the disease at a later stage.

The researchers hope their molecular map of EAE lesions will be a valuable resource for guiding future MS research. It might also be used to help identify specific molecules or pathways to target for therapeutic intervention.

“Identifying the early events that occur after inflammation and teasing apart which are reparative versus which are damaging, can potentially help us identify MS disease activity sooner and develop treatments to slow or stop its progression,” Reich says.