Spatiotemporal Analysis of Remyelination Reveals a Concerted Interferon-Responsive Glial State That Coordinates Immune Infiltration

Abstract

Remyelination, the process by which axons are re-encased in myelin after injury, is a critical step in restoring brain function, yet the dynamics from initial injury to repair remain poorly characterized. Here, we combined optimized single-nucleus RNA-seq with Slide-seqv2, a high-resolution spatial transcriptomics technology, to densely reconstruct the cellular processes that coordinate remyelination after a focal demyelinating injury. This revealed several findings: First, we found extensive transcriptional diversity of glia and monocyte-derived macrophages from demyelination to repair. Second, we identified a population of infiltrating peripheral lymphocytes--predominantly CD8 T-cells and natural killer cells--that are enriched specifically during remyelination. Third, we identified a concerted interferon-response gene signature that is shared across several cell types--microglia, astrocytes, and the oligodendrocyte lineage--just prior to reestablishment of myelin. These interferon-responsive glia (IRG) form clusters around remyelinating white matter and their formation is solely dependent on the type I interferon receptor. Functionally, we found that IRG secrete the cytokine CXCL10 which mediates infiltration of peripheral lymphocytes into the repairing white matter. Depletion of the most abundant infiltrating lymphocyte, CD8 T-cells, attenuated the differentiation of mature oligodendrocytes during remyelination. Together, our data reveals the diversity of glial-immune interactions that orchestrate white matter repair and a type I-dependent glial state that drives lymphocyte influx into damaged white matter to modulate oligodendrocyte differentiation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=57 SRC="FIGDIR/small/649486v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2c7e07org.highwire.dtl.DTLVardef@1063719org.highwire.dtl.DTLVardef@10b8862org.highwire.dtl.DTLVardef@26dd8b_HPS_FORMAT_FIGEXP M_FIG C_FIG