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- Title
The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration.
- Authors
Xiao-Feng Zhao; Huffman, Lucas D.; Hafner, Hannah; Athaiya, Mitre; Finneran, Matthew C.; Kalinski, Ashley L.; Rafi Kohen; Flynn, Corey; Passino, Ryan; Johnson, Craig N.; Kohrman, David; Riki Kawaguchi; Yang, Lynda J. S.; Twiss, Jeffery L.; Geschwind, Daniel H.; Corfas, Gabriel; Giger, Roman J.
- Abstract
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.
- Subjects
NERVE tissue; SCIATIC nerve; MONONUCLEAR leukocytes; REGENERATION (Biology); NEURODEGENERATION
- Publication
eLife, 2023, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.80881