Project description:The peripheral nerve contains diverse cell types that support its proper function and maintenance. We analyzed multiple peripheral nerves using single-nuclei RNA-sequencing (snRNA-seq), which allowed us to circumvent difficulties encountered in analyzing cells with complex morphologies via conventional single cell methods. The resultant mouse peripheral nerve cell atlas highlights a diversity of cell types, including multiple subtypes of SCs, immune cells, and stromal cells. We identified a distinct myelinating-SC subtype that expresses Cldn14, Adamtsl1, and Pmp2 and preferentially ensheathes motor axons. The number of these motor-associated, Pmp2+ SCs is reduced in both ALS SOD1G93A mouse model and human ALS nerve samples. Our findings reveal the diversity of SCs and other cell types in peripheral nerve and serve as a reference for future studies of nerve biology and disease.
Project description:The peripheral nerve contains diverse cell types that support its proper function and maintenance. We analyzed multiple peripheral nerves using single-nuclei RNA-sequencing (snRNA-seq), which allowed us to circumvent difficulties encountered in analyzing cells with complex morphologies via conventional single cell methods. The resultant mouse peripheral nerve cell atlas highlights a diversity of cell types, including multiple subtypes of SCs, immune cells, and stromal cells. We identified a distinct myelinating-SC subtype that expresses Cldn14, Adamtsl1, and Pmp2 and preferentially ensheathes motor axons. The number of these motor-associated, Pmp2+ SCs is reduced in both ALS SOD1G93A mouse model and human ALS nerve samples. Our findings reveal the diversity of SCs and other cell types in peripheral nerve and serve as a reference for future studies of nerve biology and disease.
Project description:The peripheral nervous system harbours a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate break down and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling, and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism, to provide sufficient energy for successful nerve repair.
Project description:Spiral ganglion neurons (SGNs) and the associated components of the auditory nerve are primary carriers of auditory information from hair cells to the brain. Loss of SGNs occurs with many pathological conditions, resulting in permanent sensorineural hearing loss. Neural stem/progenitors (NSPs) have been well-characterized in several locations of adult brain and retina. However, it is unclear whether NSPs are present in the adult auditory nerve. Here we examined the self-renewal potential of the adult auditory nerve using ouabain application as a well-established mouse model of acute SGN injury. The observed increase in cell proliferation, alteration in enchromatin/heterochromatin ratio and down-regulation of histone deacetylase expression in glial cells suggest that the quiescent glial cells convert to an activated state after SGN degeneration. This was further confirmed by global gene expression analysis of injured auditory nerves, which showed up-regulation of numerous neurogenesis- and/or development-associated genes shortly after ouabain exposure. These genes include molecular markers commonly used for the identification of NSPs. Under a strict culture regimen, auditory nerve-derived cells of adult mouse ears gave rise to neurospheres, suggesting that multipotent NSPs are present in adult cochlear nerve. Neurosphere assays on Sox2 transgenic mice revealed that Sox2+ glial cells are the source for NSPs. Our data also showed that acute injury or hypoxia enhances neurosphere formation. Taken together, our study revealed that glial cells of adult cochlea exhibit several NSP characteristics, and hence these mature non-neuronal cells may be important targets for promoting self-repair of degenerative auditory nerves. Auditory nerves were removed from the temporal bones of adult CBA/CaJ mice, aged 8 to 12 weeks. Tissues were either collected and used directly as the tissue samples or dissociated and used for the cell culture samples. Dissociated auditory nerve cells were propagated and grown to full confluency (5-7 days), constituting the cultured cell samples. For neurosphere samples, growth medium was changed to neurosphere formation medium and the cells were cultured for an additional 12 days. All samples were prepared in triplicate (n=3).
Project description:To investigate the potential function of lncRNAs in Schwann cell (SCs) response to sciatic nerve damage and repair, we extracted the total RNA of crushed sciatic nerves and intact contralateral nerves for RNA-sequencing (RNA-seq). A total of 98 differentially expressed lncRNAs (including 46 up-regulated and 52 down-regulated lncRNAs) and 77 differentially expressed mRNAs (including 55 up-regulated and 22 down-regulated mRNAs) were identified between crushed sciatic nerves and normal control (log 2 FC > 1 and p < 0.001).