https://elifesciences.org/articles/80881

Upon trauma, the adult murine peripheral nervous system (PNS) displays a remarkable degree of spontaneous anatomical and functional regeneration. To explore extrinsic mechanisms of neural repair, we carried out single-cell analysis of naive mouse sciatic nerve, peripheral blood mononuclear cells, and crush sciatic nerves at 1 day, 3 days, and 7 days following injury. During the first week, monocytes and macrophages (Mo/Mac) rapidly accumulate in the injured nerve and undergo extensive metabolic reprogramming. Proinflammatory Mo/Mac with a high glycolytic flux dominate the early injury response and rapidly give way to inflammation resolving Mac, programmed toward oxidative phosphorylation. Nerve crush injury causes partial leakiness of the blood-nerve barrier, proliferation of endoneurial and perineurial stromal cells, and entry of opsonizing serum proteins. Micro-dissection of the nerve injury site and distal nerve, followed by single-cell RNA-sequencing , identified distinct immune compartments, triggered by mechanical nerve wounding and Wallerian degeneration, respectively. This finding was independently confirmed with Sarm1KO mice, in which immune cells readily entered the injury site in Sarm1KO mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naive and injured PNS and report on hundreds of ligand-receptor interactions. Our longitudinal analysis represents a new resource of neural tissue regeneration, reveals location-specific immune microenvironments, and reports a large intercellular communication networks. To faciliate the mining of scRNAseq datasets, we generated the injured sciated nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/