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In adult mice, microglia depletion exacerbates injury and impairs functional recovery, suggesting that microglia play a protective role after SCI. We performed RNA sequencing on four spinal cord conditions (uninjured, injured, microglia\u2010depleted uninjured, and microglia\u2010depleted injured) to identify the core transcriptional signature of microglia\u2010dependent restorative functions after SCI. Bioinformatics analysis identified 16 genes as critical microglia\u2010dependent reparative regulators. Furthermore, our findings demonstrated that manipulating select genes and restoring core microglia\u2010dependent signaling pathways resulted in a significant reduction in lesion size, increased neuronal survival, enhanced axonal regeneration, and promoted substantial locomotor recovery in a SCI model with microglia depletion. Our findings identify key transcriptional networks that regulate microglia reparative properties in the acute phases after SCI and suggest novel microglia\u2010dependent strategies for SCI treatment.<\/jats:p>","DOI":"10.1002\/glia.70117","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T12:20:21Z","timestamp":1765974021000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Restoration of Microglia\u2010Dependent Signaling Networks Drives Tissue Repair and Functional Recovery After Spinal Cord Injury in Microglia\u2010Depleted Mice"],"prefix":"10.1002","volume":"74","author":[{"given":"Qi","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Sports Medicine The Affiliated Hospital of Qingdao University  Qingdao China"},{"name":"Qingdao Medical College of Qingdao University Qingdao University  Qingdao 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