{"doi":"10.1016/j.cell.2025.06.002","title":"Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications","abstract":"Vascular dementia (VaD), the second-leading cause of dementia, is primarily a white matter ischemic disease with no direct therapies. Cell-cell interactions within lesion sites dictate disease progression or repair. To elucidate key intercellular pathways, we employ a VaD mouse model with focal ischemia replicating many elements of the complex pathophysiology of human VaD combined with transcriptomic and functional analyses. By integrating cell-type-specific mouse VaD transcriptomes and human VaD single-nucleus RNA sequencing (snRNA-seq) data plus a custom ligand-receptor database (4,053 human and 2,032 mouse pairs), conserved dysregulated intercellular pathways in both species are identified. We demonstrate that two intercellular signaling systems, Serpine2-Lrp1 and CD39-A3AR, are disrupted in VaD. Reduced Serpine2 expression enhances oligodendrocyte progenitor cell (OPC) differentiation, promoting repair, while an A3AR-specific agonist-currently in clinical trials for psoriasis-restores tissue integrity and behavioral function in the VaD model. This study reveals intercellular signaling targets and provides a foundation for developing innovative therapies for VaD.","journal":"Cell","year":2025,"id":511072,"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":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"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":226817,"name":"Riki Kawaguchi","orcid":"0000-0002-2489-4825","position":1,"is_corresponding":false},{"id":638828,"name":"Yang Shen","orcid":"0000-0002-6055-5046","position":2,"is_corresponding":false},{"id":1343049,"name":"Michał Machnicki","orcid":null,"position":3,"is_corresponding":false},{"id":1343050,"name":"Nikole G. Villegas","orcid":null,"position":4,"is_corresponding":false},{"id":1343051,"name":"Delaney R. Cooper","orcid":null,"position":5,"is_corresponding":false},{"id":1343052,"name":"Natalia Montgomery","orcid":null,"position":6,"is_corresponding":false},{"id":1368298,"name":"Ying Cai","orcid":"0000-0001-6550-1373","position":7,"is_corresponding":false},{"id":1343053,"name":"Jacqueline Haring","orcid":null,"position":8,"is_corresponding":false},{"id":1343054,"name":"Ruirui Lan","orcid":null,"position":9,"is_corresponding":false},{"id":1343055,"name":"Angelina H. Yuan","orcid":null,"position":10,"is_corresponding":false},{"id":807721,"name":"Christopher Kwesi O. Williams","orcid":"0000-0001-9403-7207","position":11,"is_corresponding":false},{"id":245003,"name":"Shino Magaki","orcid":"0000-0003-0433-5759","position":12,"is_corresponding":false},{"id":244990,"name":"Harry V. Vinters","orcid":"0000-0002-2965-1240","position":13,"is_corresponding":false},{"id":553976,"name":"Ye Zhang","orcid":"0000-0002-1546-5930","position":14,"is_corresponding":false},{"id":828561,"name":"Lindsay M. De Biase","orcid":"0000-0003-0177-5601","position":15,"is_corresponding":false},{"id":681420,"name":"Alcino J. Silva","orcid":"0000-0002-1587-4558","position":16,"is_corresponding":false},{"id":237102,"name":"S. Thomas Carmichael","orcid":"0000-0002-1169-9203","position":17,"is_corresponding":false},{"id":1342766,"name":"Min Tian","orcid":"0000-0003-0460-4584","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T02:47:50.575618Z","pmid":"40592323","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":[]}