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New Tool for Studying Cell Subsets Uncovers Potential Therapeutic Target for MS

Using a novel technique for the isolation and analysis of rare cell types, a team led by scientists from Harvard Medical School and the University of California, San Francisco, have identified a mechanism that could potentially be targeted to treat multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. While previous single-cell sequencing effort identified subsets of astrocytes involved in the pathogenesis of MS and its model experimental autoimmune encephalomyelitis (EAE), there is a dearth of unique surface markers for the isolation of astrocyte subsets. This, along with the rarity of pathogenic astrocytes, has hampered the analysis and the identification of candidate therapeutic targets. To address this, the team developed FIND-seq, a high-throughput microfluidic cytometry method that combines encapsulation of cells in droplets, PCR-based detection of target nucleic acids, and droplet sorting to enable in-depth transcriptomic analyses of cells of interest at single-cell resolution. As they reported in Nature this week, they used the approach to study the regulation of astrocytes characterized by the splicing-driven activation of the transcription factor XBP1, which promotes disease pathology in MS and EAE. When combined with cell-specific genetic perturbation studies in vivo, and bulk and single-cell transcriptional and genomic analyses of MS and EAE samples, FIND-seq uncovered a role for the nuclear receptor NR3C2 and its corepressor NCOR2 in limiting XBP1-driven pathogenic astrocyte responses. The work, the researchers write, highlights the potential for FIND-seq as a tool for the investigation of cell subsets identified in single-cell genomic studies.