Stage-Specific Gene Expression Profiles in Multiple Sclerosis Cortical Lesions Identified via Spatial Transcriptomics

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by demyelinating lesions in the central nervous system. While animal models have provided insights into lesion development, human-based studies remain limited. This study investigated the molecular landscape of gray matter lesions at different stages using spatial transcriptomics. Post-mortem cortical tissue from MS patients was analyzed to examine gene expression in lesions classified as early active, chronic active, or chronic inactive based on myelin integrity and macrophage/microglia activity. Distinct transcriptomic profiles were observed across lesion stages, although these findings should be considered exploratory given the limited sample size, with the early active category represented by a single lesion. The early active lesion showed increased expression of immune-related genes (e.g., HLA-DRA, CD68, CCL5) and enrichment of inflammatory and extracellular matrix remodeling pathways. Chronic active lesions showed enrichment of innate immune pathways, including Toll-like receptor and complement signaling, whereas chronic inactive lesions exhibited increased expression of heat shock proteins (HSPA1A, HSPA1B), and stress-response pathways. Control samples showed preserved neuronal and myelin gene expression. These findings provide preliminary insights into molecular processes that may be associated with MS lesion progression and may identify candidate biomarkers for future validation studies.