September 29, 2021

Barcoded single-cell viral tracing of astrocyte-microglia interactions in CNS inflammation

Michael Wheeler, PhD

Additional Authors: *Clark IC, *Gutiérrez-Vázquez C, *Wheeler MA, Li Z, Rothhammer V, Linnerbauer M, Sanmarco LM, Guo L, Blain M, Zandee SEJ, Chao C-C, Batterman KV, Schwabenland M, Lotfy P, Tejeda Velarde A, Hewson P, Polonio CM, Shultis MW, Salem Y, Tjon EC, Fonseca-Castro PH, Borucki DM, Alves de Lima K, Plasencia A, Abate AR, Rosene DL, Hodgetts KJ, Prinz M, Antel JP, Prat A, Quintana FJ. *Co-first authors.

Cell-cell interactions control central nervous system (CNS) physiology and pathology. To study astrocyte cell interactions in vivo, we developed Rabies Barcode Interaction Detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA-sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and EphrinB3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia pro-inflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.

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