{"doi":"10.1101/2025.04.22.649486","title":"Spatiotemporal Analysis of Remyelination Reveals a Concerted Interferon-Responsive Glial State That Coordinates Immune Infiltration","abstract":"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. Abstract Figure","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":554881,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9436,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1453161,"name":"Raphael Rakosi-Schmidt","orcid":null,"position":1,"is_corresponding":false},{"id":1226735,"name":"Eric García","orcid":null,"position":2,"is_corresponding":false},{"id":1453162,"name":"Yuesang Lin","orcid":null,"position":3,"is_corresponding":false},{"id":59100,"name":"Naeem Nadaf","orcid":"0000-0002-7805-8523","position":4,"is_corresponding":false},{"id":1327346,"name":"Jessica Dixon","orcid":null,"position":5,"is_corresponding":false},{"id":1453163,"name":"Shiran Guo","orcid":null,"position":6,"is_corresponding":false},{"id":313633,"name":"Nader Morshed","orcid":"0000-0002-0346-9651","position":7,"is_corresponding":false},{"id":1452743,"name":"Constanze Depp","orcid":"0000-0003-2868-6932","position":8,"is_corresponding":false},{"id":1453164,"name":"Jordan Doman","orcid":null,"position":9,"is_corresponding":false},{"id":1453165,"name":"Judy Xia","orcid":null,"position":10,"is_corresponding":false},{"id":1452744,"name":"Henna Jäntti","orcid":"0000-0003-3005-407X","position":11,"is_corresponding":false},{"id":228573,"name":"Beth Stevens","orcid":"0000-0003-4226-1201","position":12,"is_corresponding":false},{"id":3628,"name":"Evan Z. Macosko","orcid":"0000-0002-2794-5165","position":13,"is_corresponding":false},{"id":984775,"name":"Michael-John Dolan","orcid":"0000-0001-9666-3682","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:54:54.542303Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}