Journal Article

The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration

Finneran, Matthew C, Passino, Ryan, Corfas, Gabriel, Kawaguchi, Riki, Twiss, Jeffery L, Giger, Roman J, Hafner, Hannah, Huffman, Lucas D, Flynn, Corey, Geschwind, Daniel H, Kohrman, David, Athaiya, Mitre, Yang, Lynda JS, Johnson, Craig N, Kalinski, Ashley L, Kohen, Rafi, Zhao, Xiao-Feng

2022

Overview

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/ .

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Analysis / Animal experimentation / Animals / Armadillo Domain Proteins - metabolism / Blood proteins / Cell proliferation / Chemokines / Communication / Comparative analysis / Cyclin-dependent kinases / Cytoskeletal Proteins - metabolism / Dendritic cells / Fibroblasts / Gene expression / Glycolysis / Immunology and Inflammation / Inflammation / Kinases / Leukocytes, Mononuclear / Longitudinal studies / Macrophages / Metabolism / Mice / Microenvironments / Monocytes / Nerve Crush / Nerve Degeneration / Nerve Regeneration / Nervous system / Neurodegeneration / Neuroscience / Neutrophils / Oxidative phosphorylation / parabiosis / Peripheral blood mononuclear cells / Peripheral Nerve Injuries - metabolism / Phosphorylation / Physiological aspects / Regeneration / Sciatic nerve / Sciatic Nerve - metabolism / Serum proteins / single-cell RNA seq / Stromal cells / Trauma / Wallerian degeneration / Wallerian Degeneration - metabolism / Wallerian Degeneration - pathology / Wounding