Restoration of Microglia‐Dependent Signaling Networks Drives Tissue Repair and Functional Recovery After Spinal Cord Injury in Microglia‐Depleted Mice

ABSTRACT Regulatory mechanisms underlying microglia‐dependent restorative effects during the early stages following spinal cord injury (SCI) remain uncertain. 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‐depleted uninjured, and microglia‐depleted injured) to identify the core transcriptional signature of microglia‐dependent restorative functions after SCI. Bioinformatics analysis identified 16 genes as critical microglia‐dependent reparative regulators. Furthermore, our findings demonstrated that manipulating select genes and restoring core microglia‐dependent 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‐dependent strategies for SCI treatment.