The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration.
The injured sciatic nerve atlas (iSNAT), insights into the cellular and molecular basis of neural tissue degeneration and regeneration.
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DOI：
10.7554/elife.80881
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发表时间：
2022-12-14
期刊：
影响因子：
7.7
通讯作者：
Giger RJ
中科院分区：
文献类型：
--
作者：
Zhao XF;Huffman LD;Hafner H;Athaiya M;Finneran MC;Kalinski AL;Kohen R;Flynn C;Passino R;Johnson CN;Kohrman D;Kawaguchi R;Yang LJS;Twiss JL;Geschwind DH;Corfas G;Giger RJ
成年小鼠周围神经系统(PNS)在创伤后表现出显著程度的自发性解剖和功能再生。为了探索神经修复的外在机制，我们对幼稚的小鼠坐骨神经、外周血单核细胞以及损伤后1天、3天和7天的坐骨神经进行了单细胞分析。在第一周，单核细胞和巨噬细胞(Mo/Mac)在损伤的神经中迅速积聚，并经历广泛的代谢重新编程。具有高糖酵解通量的促炎Mo/Mac在早期的损伤反应中占据主导地位，并迅速让位于炎症分解Mac，编程为氧化磷酸化。神经挤压损伤导致血-神经屏障的部分渗漏，神经内和神经周围基质细胞的增殖，以及调理血清蛋白的进入。对神经损伤部位和远端神经进行显微解剖，然后进行单细胞RNA测序，鉴定出分别由机械性神经损伤和沃勒变性引发的不同免疫区段。这一发现在Sarm1-/-小鼠中得到了独立证实，在Sarm1-/-小鼠中，沃勒变性大大延迟。用嵌合小鼠进行的实验表明，在Sarm1-/-小鼠中，野生型免疫细胞很容易进入损伤部位，但在远端神经中稀疏，除了Mo。我们使用CellChat来探索幼稚和受损的三叉神经节的细胞间通讯，并报告了数百种配体-受体的相互作用。我们的纵向分析代表了神经组织再生的新资源，揭示了特定位置的免疫微环境，并报告了大型细胞间通信网络。为了便于挖掘scRNAseq数据集，我们生成了损伤的坐骨神经图谱(ISNAT)：https://cdb-rshiny.med.umich.edu/Giger_iSNAT/.
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/.