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Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity.

ABSTRACT: Peripheral nerves contain axons and their enwrapping glia cells named Schwann cells (SCs) that are either myelinating (mySCs) or nonmyelinating (nmSCs). Our understanding of other cells in the peripheral nervous system (PNS) remains limited. Here, we provide an unbiased single cell transcriptomic characterization of the nondiseased rodent PNS. We identified and independently confirmed markers of previously underappreciated nmSCs and nerve-associated fibroblasts. We also found and characterized two distinct populations of nerve-resident homeostatic myeloid cells that transcriptionally differed from central nervous system microglia. In a model of chronic autoimmune neuritis, homeostatic myeloid cells were outnumbered by infiltrating lymphocytes which modulated the local cell-cell interactome and induced a specific transcriptional response in glia cells. This response was partially shared between the peripheral and central nervous system glia, indicating common immunological features across different parts of the nervous system. Our study thus identifies subtypes and cell-type markers of PNS cells and a partially conserved autoimmunity module induced in glia cells.

SUBMITTER: Wolbert J

PROVIDER: S-EPMC7196786 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity.

Wolbert Jolien J Li Xiaolin X Heming Michael M Mausberg Anne K AK Akkermann Dagmar D Frydrychowicz Clara C Fledrich Robert R Groeneweg Linda L Schulz Christian C Stettner Mark M Alonso Gonzalez Noelia N Wiendl Heinz H Stassart Ruth R Meyer Zu Hörste Gerd G

Proceedings of the National Academy of Sciences of the United States of America 20200415 17

Peripheral nerves contain axons and their enwrapping glia cells named Schwann cells (SCs) that are either myelinating (mySCs) or nonmyelinating (nmSCs). Our understanding of other cells in the peripheral nervous system (PNS) remains limited. Here, we provide an unbiased single cell transcriptomic characterization of the nondiseased rodent PNS. We identified and independently confirmed markers of previously underappreciated nmSCs and nerve-associated fibroblasts. We also found and characterized t ...[more]

PMID: 32295886

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Project description:Skeletal muscle-derived cells have strong secretory function, while skeletal muscle-derived stem cells, which are included in muscle-derived cells, can differentiate into Schwann cell-like cells and other cell types. However, the effect of muscle-derived cells on peripheral nerve defects has not been reported. In this study, 5-mm-long nerve defects were created in the right sciatic nerves of mice to construct a peripheral nerve defect model. Adult female C57BL/6 mice were randomly divided into four groups. For the muscle-derived cell group, muscle-derived cells were injected into the catheter after the cut nerve ends were bridged with a polyurethane catheter. For external oblique muscle-fabricated nerve conduit and polyurethane groups, an external oblique muscle-fabricated nerve conduit or polyurethane catheter was used to bridge the cut nerve ends, respectively. For the sham group, the sciatic nerves on the right side were separated but not excised. At 8 and 12 weeks post-surgery, distributions of axons and myelin sheaths were observed, and the nerve diameter was calculated using immunofluorescence staining. The number, diameter, and thickness of myelinated nerve fibers were detected by toluidine blue staining and transmission electron microscopy. Muscle fiber area ratios were calculated by Masson's trichrome staining of gastrocnemius muscle sections. Sciatic functional index was recorded using walking footprint analysis at 4, 8, and 12 weeks after operation. The results showed that, at 8 and 12 weeks after surgery, myelin sheaths and axons of regenerating nerves were evenly distributed in the muscle-derived cell group. The number, diameter, and myelin sheath thickness of myelinated nerve fibers, as well as gastrocnemius muscle wet weight and muscle area ratio, were significantly higher in the muscle-derived cell group compared with the polyurethane group. At 4, 8, and 12 weeks post-surgery, sciatic functional index was notably increased in the muscle-derived cell group compared with the polyurethane group. These criteria of the muscle-derived cell group were not significantly different from the external oblique muscle-fabricated nerve conduit group. Collectively, these data suggest that muscle-derived cells effectively accelerated peripheral nerve regeneration. This study was approved by the Animal Ethics Committee of Plastic Surgery Hospital, Chinese Academy of Medical Sciences (approval No. 040) on September 28, 2016.

Project description:BackgroundEfficient and stable delivery of neurotrophic factors (NTFs) is crucial to provide suitable microenvironment for peripheral nerve regeneration. Neurotrophin-3 (NT-3) is an important NTF during peripheral nerve regeneration which is scarce in the first few weeks of nerve defect. Exosomes are nanovesicles and have been served as promising candidate for biocarrier. In this work, NT-3 mRNA was encapsulated in adipose-derived stem cell (ADSC)-derived exosomes (ExoNT-3). These engineered exosomes were applied as NT-3 mRNA carrier and then were loaded in nerve guidance conduit (ExoNT-3-NGC) to bridge rat sciatic nerve defect.MethodNT-3 mRNA was encapsulated in exosomes by forcedly expression of NT-3 mRNA in the donor ADSCs. ExoNT-3 were co-cultured with SCs in vitro; after 24 h of culture, the efficiency of NT-3 mRNA delivery was evaluated by qPCR, western blotting and ELISA. Then, ExoNT-3 were loaded in alginate hydrogel to construct the nerve guidance conduits (ExoNT-3-NGC). ExoNT-3-NGC were implanted in vivo to reconstruct 10 mm rat sciatic nerve defect. The expression of NT-3 was measured 2 weeks after the implantation operation. The sciatic nerve functional index (SFI) was examined at 2 and 8 weeks after the operation. Moreover, the therapeutic effect of ExoNT-3-NGC was also evaluated by morphology assay, immunofluorescence staining of regenerated nerves, function evaluation of gastrocnemius muscles after 8 weeks of implantation.ResultsThe engineered exosomes could deliver NT-3 mRNA to the recipient cells efficiently and translated into functional protein. The constructed NGC could realize stable release of exosomes at least for 2 weeks. After NGC implantation in vivo, ExoNT-3-NGC group significantly promote nerve regeneration and improve the function recovery of gastrocnemius muscles compared with control exosomes (Exoempty-NGC) group.ConclusionIn this work, NGC was constructed to allow exosome-mediated NT-3 mRNA delivery. After ExoNT-3-NGC implantation in vivo, the level of NT-3 could restore which enhance the nerve regeneration. Our study provide a potential approach to improve nerve regeneration.

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Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity.

Publications

Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity.

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