Spatial mapping of MS-related lesions may be effective as diagnostic, therapeutic tool

Key takeaways:

• Researchers utilized iterative indirect immunofluorescent imaging to examine MS lesion tissue.
• Lesion mapping yielded a high degree of specificity in locating inhibiting mechanisms to remyelination.

WEST PALM BEACH, Fla. — Spatial mapping of lesional tissue is a precise method to identify key functional interactions that may lead to successful therapeutic intervention in multiple sclerosis, according to a presenter at ACTRIMS 2024.

“In this project we were using spatial profiling of MS tissue to identify the interactions between the cells that are relevant to remyelination failure,” Milos Opacic, PhD, a postdoctoral associate in the department of neurology at Yale School of Medicine, stated in his presentation.

As remyelination remains a critical unmet therapeutic need in MS, Opacic and colleagues utilized highly multiplexed imaging of MS lesions to determine spatial interactions within the functional interactome to identify the inhibitory pathways that lead to remyelination failure and identify dormant pro-myelinating pathways that may respond to therapeutic stimulation.

Their imaging study involved the use of iterative indirect immunofluorescent imaging (4i) to examine MS lesion tissue via and antibody panel designed to capture different cell types and snRNA-Seq derived cellular subpopulations.

The researchers then employed a computational analysis pipeline to identify spatially interacting cell populations and functional receptor-ligand (R-L) interactions between neighboring cells, while also generating spatial multiomic maps of different stages of white matter lesion evolution, i.e. acute, post-demyelinating, chronic active, chronic silent and remyelinating.

When the researchers focused on a specific subpopulation of pre-myelinating oligodendrocytes (OLpre-m), a high degree of prevalence was found in remyelinating lesions, which was absent in chronic silent lesions. In chronic active lesions, more OLpre-m were located near the center or rim of the lesions, where they exhibited high cellular stress levels. OLpre-m were also close to senescent, reactive and inflamed astrocytes, while they interacted predominantly with perinodal astrocytes in the rim and normal-appearing white matter.

Data further showed imaging allowed Opacic and colleagues to identify cytotoxic and inflammatory R-L interactions between OLpre-m and surrounding cells exclusive to the lesion center, which may explain increased stress levels in OLpre-m in the outer layer of the lesion center as well as their absence within the center.

“We found that the highest-ranking inhibitory mechanisms were serotonin receptor signaling followed by the G-protein 37 signaling, and these pathways took place in the center and the interacting cells were reactive and inflamed,” Opacic said.