Microglia coordinate cellular interactions during spinal cord repair in mice

• Published in: Nature communications 2022-07, Vol.13 (1), p.4096-20, Article 4096
• Main Authors: Brennan, Faith H., Li, Yang, Wang, Cankun, Ma, Anjun, Guo, Qi, Li, Yi, Pukos, Nicole, Campbell, Warren A., Witcher, Kristina G., Guan, Zhen, Kigerl, Kristina A., Hall, Jodie C. E., Godbout, Jonathan P., Fischer, Andy J., McTigue, Dana M., He, Zhigang, Ma, Qin, Popovich, Phillip G.
• Format: Article
• Language: English
• Subjects: 13/1; 13/31; 13/51; 14/19; 14/63; 38/90; 38/91; 631/378/2596/1953; 631/378/371; 64/60; Animals; Astrocytes; Bioinformatics; Damage prevention; Depletion; Gene sequencing; Humanities and Social Sciences; Inflammation; Inflammatory response; Leukocytes; Macrophages; Macrophages - pathology; Mice; Mice, Inbred C57BL; Microglia; Microglia - pathology; Monocytes; multidisciplinary; Recovery of function; Repair; Science; Science (multidisciplinary); Spinal Cord - pathology; Spinal Cord Injuries; Spinal Cord Regeneration; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31797-0

Traumatic spinal cord injury (SCI) triggers a neuro-inflammatory response dominated by tissue-resident microglia and monocyte derived macrophages (MDMs). Since activated microglia and MDMs are morphologically identical and express similar phenotypic markers in vivo, identifying injury responses specifically coordinated by microglia has historically been challenging. Here, we pharmacologically depleted microglia and use anatomical, histopathological, tract tracing, bulk and single cell RNA sequencing to reveal the cellular and molecular responses to SCI controlled by microglia. We show that microglia are vital for SCI recovery and coordinate injury responses in CNS-resident glia and infiltrating leukocytes. Depleting microglia exacerbates tissue damage and worsens functional recovery. Conversely, restoring select microglia-dependent signaling axes, identified through sequencing data, in microglia depleted mice prevents secondary damage and promotes recovery. Additional bioinformatics analyses reveal that optimal repair after SCI might be achieved by co-opting key ligand-receptor interactions between microglia, astrocytes and MDMs. Here the authors show, using microglia-specific depletion techniques and single cell transcriptomics, that optimal repair after murine spinal cord injury (SCI) requires microglia.