TY - JOUR TI - The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration AU - Zhao, Xiao-Feng AU - Huffman, Lucas D AU - Hafner, Hannah AU - Athaiya, Mitre AU - Finneran, Matthew C AU - Kalinski, Ashley L AU - Kohen, Rafi AU - Flynn, Corey AU - Passino, Ryan AU - Johnson, Craig N AU - Kohrman, David AU - Kawaguchi, Riki AU - Yang, Lynda JS AU - Twiss, Jeffery L AU - Geschwind, Daniel H AU - Corfas, Gabriel AU - Giger, Roman J A2 - Stevens, Beth A2 - Rothlin, Carla V A2 - Simons, Mikael A2 - Carter, Bruce D VL - 11 PY - 2022 DA - 2022/12/14 SP - e80881 C1 - eLife 2022;11:e80881 DO - 10.7554/eLife.80881 UR - https://doi.org/10.7554/eLife.80881 AB - 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 naïve mouse sciatic nerve, peripheral blood mononuclear cells, and crushed 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 Sarm1-/- mice, in which Wallerian degeneration is greatly delayed. Experiments with chimeric mice showed that wildtype immune cells readily enter the injury site in Sarm1-/- mice, but are sparse in the distal nerve, except for Mo. We used CellChat to explore intercellular communications in the naïve and injured PNS and report on hundreds of ligand–receptor interactions. Our longitudinal analysis represents a new resource for neural tissue regeneration, reveals location- specific immune microenvironments, and reports on large intercellular communication networks. To facilitate mining of scRNAseq datasets, we generated the injured sciatic nerve atlas (iSNAT): https://cdb-rshiny.med.umich.edu/Giger_iSNAT/. KW - sciatic nerve KW - regeneration KW - single-cell RNA seq KW - inflammation KW - Wallerian degeneration KW - parabiosis JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -