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

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.