Diversified transcriptional responses of myeloid and glial cells in spinal cord injury shaped by HDAC3 activity
The innate immunity influences neural repair after spinal cord injury (SCI). Here, we combined myeloid-specific nuclear transcriptomics and single-cell RNA-sequencing to uncover a common core but also temporally distinct gene programs in injury-activated microglia and macrophages (IAM). Intriguingly, we detected a wide range of microglial activation states even in healthy spinal cord; upon injury, reactive microglia and infiltrated macrophages progressively acquired an overall reparative, yet highly diversified gene expression profile, while maintaining their distinct transcriptional identities. Microglia and macrophages each comprise four distinct transcriptional subtypes with specialized tasks. Notably, IAM and disease-associated microglia (DAM) shared similar gene signatures, with a predominant enrichment in infiltrating macrophages and only a small subset of reactive microglia that specialized in phagocytosis, autophagy, and TyroBP network activity. We also identified an immediate response microglial subtype that may serve as source population for microglial transformation, and a highly proliferative subtype that is controlled by the epigenetic regulator HDAC3. Together, our data unveiled diversification of myeloid and other glial cell types and an extensive influence of HDAC3, which may be exploited to enhance neural repair. Overall design: Studying single cells collected from HDAC3i and Vehicle treated spinal cord 5 days post injury in mice