Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States; Neuroscience Graduate Program, University of Michigan–Ann Arbor, Ann Arbor, United States
Hannah Hafner
Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
Mitre Athaiya
Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States; Neuroscience Graduate Program, University of Michigan–Ann Arbor, Ann Arbor, United States
Matthew C Finneran
Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States; Neuroscience Graduate Program, University of Michigan–Ann Arbor, Ann Arbor, United States
Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
Rafi Kohen
Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States; Neuroscience Graduate Program, University of Michigan–Ann Arbor, Ann Arbor, United States
Department of Neurology, Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Department of Human Genetics,David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States; Institute of Precision Health, University of California, Los Angeles, Los Angeles, United States
Neuroscience Graduate Program, University of Michigan–Ann Arbor, Ann Arbor, United States; Kresge Hearing Institute, University of Michigan–Ann Arbor, Ann Arbor, United States; Department of Neurology, University of Michigan–Ann Arbor, Ann Arbor, United States
Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States; Neuroscience Graduate Program, University of Michigan–Ann Arbor, Ann Arbor, United States; Department of Neurology, University of Michigan–Ann Arbor, Ann Arbor, United States
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/.
