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Disentangling glial diversity in peripheral nerves at single-nuclei resolution

Nature Neuroscience volume 25, pages 238–251 (2022)Cite this article

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Abstract

The peripheral nerve contains diverse cell types that support its proper function and maintenance. In this study, we analyzed multiple peripheral nerves using single-nuclei RNA sequencing, 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 Schwann cells (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 an amyotrophic lateral sclerosis (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.

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Fig. 1: Generation of a single-nuclei expression atlas of mouse sciatic nerve.
Fig. 2: EFs express nmSC markers.
Fig. 3: Single-nuclei transcriptional profiling of peroneal, sural and vagus nerves highlights SCN7A as a potential DPN risk gene.
Fig. 4: Identification of SC subpopulations using multiple transcriptional profiling approaches.
Fig. 5: PMP2+ SC subpopulation is associated with thickly myelinated axons.
Fig. 6: PMP2+ SCs preferentially ensheath motor axons.
Fig. 7: Significant reduction of motor-associated SCs in ALS SOD1G93A mouse model.
Fig. 8: Pmp2-depleted fascicles identified in sciatic nerve of patients with ALS.

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Data availability

A total of 24 files, including 18 raw sequencing reads and six processed data such as expression matrices and RDS files for single-cell and single-nuclei atlases, have been deposited in the Gene Expression Omnibus repository under the reference series ID GSE182099. The Mpz-RiboTag and bulk RNA-seq data can be accessed through the sub-series ID GSE181858, and the single-nuclei data can be obtained through GSE182098. The glia portal can also be accessed through the link http://milbrandt.wustl.edu/glia-portal/. Source data are provided with this paper.

Code availability

The source code for data analysis and visualization in this study will be available online at https://github.com/aldrinyim/PNS-glia.

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Acknowledgements

The authors thank all our collaborators at the Washington University School of Medicine for their advice and discussion. We thank R. Head, R. Barve and P. Cliften at GTAC@MGI and the McDonnell Genome Institute for discussion and assistance with RNA-seq. The authors are grateful for assistance from G. Randolph’s laboratory and B. Zinselmeyer for confocal imaging and use of equipment (supported by National Institutes of Health (NIH) grants R01DK119147 and R37AI049653 to G.R.). The authors thank M. Shabsovich, T. Shen and C. Kreple for ALS SOD1G93A mice, M. Ireland for curating patient samples (supported by NIH grant R01NS078398 to T.M.) and R. Schmidt for curating clinical pathology reports and many helpful discussions. The authors thank R. McClarney and C. Menendez for experimental assistance and members of the Milbrandt and DiAntonio laboratories for helpful comments and discussion. This project was supported by NIH grants RF1MH117070 and RO1GM123203 to R.D.M. and R01NS105645 and R01AG013730 to J.M.

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  1. These authors contributed equally: Aldrin K. Y. Yim, Peter L. Wang.

Authors and Affiliations

  1. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA

    Aldrin K. Y. Yim, Peter L. Wang, John R. Bermingham Jr, Amber Hackett, Amy Strickland, Robi D. Mitra & Jeffrey Milbrandt

  2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Peter L. Wang

  3. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

    Timothy M. Miller & Cindy Ly

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Contributions

A.Y. designed and performed both the animal and sequencing experiments, derived the nuclei isolation protocol, analyzed both sequencing and imaging data and wrote the manuscript. P.L.W. designed and performed the animal experiments, analyzed the imaging data and wrote the manuscript. J.R.B. and A.S. performed the RiboTag experiments; A.S. helped with the animal experiments; and J.R.B. helped with RNA FISH experiments. A.H. helped with the animal experiments. C.L. and T.M. prepared the ALS animal and human samples. R.M. and J.M. designed and supervised the experiments, acquired funding and edited the manuscript.

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Correspondence to Jeffrey Milbrandt.

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J.M. is a cofounder, consultant and shareholder of Disarm Therapeutics, a wholly owned subsidiary of Eli Lilly & Company. All other authors declare no competing financial interests.

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Nature Neuroscience thanks Goncalo Castelo-Branco and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Generation and analysis of sciatic nerve and immune cell atlases.

(a) Gating strategy for sorting GFP+ nuclei from Sun1-GFP/+:Act-Cre/+ sciatic nerves. Nuclei were isolated from single cell suspensions containing pooled sciatic nerves from at least 5 Sun1-GFP/+:Act-Cre/+ mice. Purified nuclei were selected based on GFP and Hoechst expression. (b-f) Intronic reads contain biological information. Single nuclei atlases were generated by using either exonic or intronic reads, and CCA analysis was performed to align the two data sets. (b) The two atlases showed high level of concordance. c-f, Contribution of intronic reads to signature genes in nmSCs. (c) Csmd1 and (d) Scn7a were found to mark nmSCs. (e) Over 90% of the UMIs were from intronic reads for Csmd1. (f) Approximately 60% of the UMIs were from intronic reads for Scn7a. (g) Gating strategy for sorting CD45+ cells from sciatic nerves. Sciatic nerves were pooled from 20 Cx3cr1-GFP/+ mice and prepared for FACS sorting. Cells were stained with Propidium Iodide (PI) to select for viable cells, and with CD45 antibody to select for CD45+ population. (h) Expression of lymphangiogenesis-related genes in epineurial fibroblasts. Adamts3, Adamts14, Ccbe1, Pdgfra and Adamts12 expression in the ActB-Sun1 sciatic nerve atlas.

Extended Data Fig. 2 Generation and analysis of Mpz-enriched single nuclei atlas.

(a) Gating strategy for sorting GFP+ nuclei from Sun1-GFP/+:Mpz-Cre/+ mice. Nuclei were isolated from single cell suspensions containing pooled sciatic nerves from at least 5 Sun1-GFP/+:Act-Cre/+ mice. Purified nuclei were selected based on GFP and Hoechst expression. (b) tSNE plot with 3,047 nuclei from Sun1-GFP/+;Mpz-Cre/+ defines three GFP+ cell types – endoneurial fibroblasts, nmSCs and mSCs. (c) Differential expression analysis from Mpz-Sun1 atlas shows signature gene expression that defines endoneurial fibroblasts, including Col15a1, Lama2 and Egfr. Each column represents a gene and each row represents a nucleus, genes with high expression level are shown in yellow and low expression in purple. (d) GO analysis showing that endoneurial fibroblast markers (122 genes) are enriched for components related to collagen-containing extracellular matrix, extracellular matrix and formation of axon, neurons and synapse, percentage of GO recovery is plotted against the false discovery rate (FDR) and selected GO terms are highlighted in color. (e,f) RNA-FISH analysis of Prx, Ngfr, and Cd34 expression. (scale bar=50um) e, Representative expression of Prx and Ngfr, indicating that myelinating Schwann cells do not express Ngfr. f, Representative expression of Prx and Cd34, indicating that myelinating Schwann cells do not express Cd34. (g) RNA-FISH analysis of Csmd1 and Scn7a. Representative overlapping expression of Csmd1 (green) and Scn7a (red) in adult sciatic nerves (scale bar=50um).

Extended Data Fig. 3 Pathway-based transcriptional module analysis.

(a) Expression of all genes in the axon guidance pathway (map04360) defined by the KEGG database are shown in here, with red indicating high expression and blue indicate no expression. Many of the genes are more abundantly expressed in the Pmp2+ mSCs. (b) tSNE plot showing the expression of genes in the axon guidance pathway. (c) tSNE plot showing the expression of genes in fatty acid biosynthesis pathway (map00061). (d) tSNE plot showing the expression of genes in the sphingolipid signaling pathway (map04071).

Extended Data Fig. 4 Pmp2+ Schwann cells preferentially ensheath Chat+ axons.

(a) Validation of ChAT-Cre-tdT expression specificity. Representative expression of PMP2 (yellow) and ChAT-Ab (white) in ChAT-Cre-tdT (red) sciatic nerves. The two panels on the right have shown almost complete overlap between the antibody (white) and tdT reporter (red) for ChAT (scale bar = 50um, n = 3 biologically independent mice). (b) ChAT+ axons are mostly ensheathed by Pmp2+ SCs. Representative imaging showing the expression of MBP (blue) and PMP2 (green) in ChAT-tdT (red) sciatic nerve. (scale bar = 50um, n = 3 biologically independent mice). (c) Quantification of percentage of ChAT+ axons ensheathed by a Pmp2+ SCs in three different nerve types. Two-way ANOVA with multiple comparisons. Sciatic vs Sural: P = 0.0159, Sciatic vs Femoral: P = 0.0456, Sural vs Femoral: P = 0.0009. Data are mean+/− SD (n = 3 biologically independent mice).

Source data

Extended Data Fig. 5 SOD1G93A mice show reduced PMP2 expression in SCs.

Representative imaging of PMP2+ SCs (yellow), b-TUB+ axons (cyan) and MBP+ SCs (gray) in sciatic, femoral, and sural nerves in SOD1G93A mice. Note that femoral nerve is severely degenerated as shown by MBP staining. Sciatic nerve remains relatively intact with depletion of PMP2, while sural nerve has intact axons with MBP+ SCs ensheathing them (scale bar = 50um, n = 3 biologically independent mice).

Supplementary information

Supplementary Information

Supplementary Figs. 1–8 and Supplementary Table 3

Reporting Summary

Supplementary Table 1

SC-enriched atlas. Differential expression analysis

Supplementary Table 2

KEGG expression module analysis

Supplementary Table 4

Hereditary peripheral neuropathic genes

Supplementary Table 5

List of RNA FISH probes

Source data

Source Data Fig. 5

Statistical Source Data

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Source Data Fig. 7

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Source Data Extended Data Fig. 4

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Yim, A.K.Y., Wang, P.L., Bermingham, J.R. et al. Disentangling glial diversity in peripheral nerves at single-nuclei resolution. Nat Neurosci 25, 238–251 (2022). https://doi.org/10.1038/s41593-021-01005-1

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