4D marmoset brain map reveals MRI and molecular signatures for onset of multiple sclerosis–like lesions [spatial transcriptomes]

ABSTRACT: Abstract: The cellular and molecular dynamics of multiple sclerosis (MS) lesion development and repair cannot be inferred through study of postmortem tissue harvested decades after lesion onset. Employing MRI-informed spatiotemporal RNA profiling and experimental autoimmune encephalitis (EAE) in the common marmoset — a faithful model for these processes — we identified five microenvironmental groups pertinent to neural function, immune and glial responses, tissue destruction and repair, and regulatory networks at brain borders during lesion evolution. Before visible demyelination, astrocytic and ependymal secretory signals delineated perivascular and periventricular regions, later becoming demyelination hotspots where MS-like lesions frequently grow. An MRI biomarker, the ratio of proton density-weighted signal to T1 relaxation time, captured the hypercellularity phase before apparent myelin destruction. At lesion onset, there was a global shift in cellular connectivity, especially in extracellular matrix-mediated signaling. Early responses included microglia and oligodendrocyte precursor cell proliferation and diversification, replaced by monocyte derivatives and lingering lymphocytes as lesions aged. Concurrent with demyelination, reparative signaling modules were found at the lesion edge as early as 10 days post-lesion establishment. Over-representation of senescence-associated secretory phenotype at the brain borders and the formation of concentric glial barriers at the lesion edge prompted model-based identification of potential treatments to reverse EAE-associated molecular pathology. Our study highlights the marmoset platform's potential for assessing MS treatment outcomes.

ORGANISM(S): Callithrix jacchus

PROVIDER: GSE266655 | GEO | 2025/02/28

REPOSITORIES: GEO