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Published September 1, 2022 | Supplemental Material + In Press
Journal Article Open

Schwann cell precursors represent a neural crest‐like state with biased multipotency

Abstract

Schwann cell precursors (SCPs) are nerve-associated progenitors that can generate myelinating and non-myelinating Schwann cells but also are multipotent like the neural crest cells from which they originate. SCPs are omnipresent along outgrowing peripheral nerves throughout the body of vertebrate embryos. By using single-cell transcriptomics to generate a gene expression atlas of the entire neural crest lineage, we show that early SCPs and late migratory crest cells have similar transcriptional profiles characterised by a multipotent "hub" state containing cells biased towards traditional neural crest fates. SCPs keep diverging from the neural crest after being primed towards terminal Schwann cells and other fates, with different subtypes residing in distinct anatomical locations. Functional experiments using CRISPR-Cas9 loss-of-function further show that knockout of the common "hub" gene Sox8 causes defects in neural crest-derived cells along peripheral nerves by facilitating differentiation of SCPs towards sympathoadrenal fates. Finally, specific tumour populations found in melanoma, neurofibroma and neuroblastoma map to different stages of SCP/Schwann cell development. Overall, SCPs resemble migrating neural crest cells that maintain multipotency and become transcriptionally primed towards distinct lineages.

Additional Information

©2022 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Received: 20 May 2021. Accepted: 15 June 2022. Published: 11 July 2022. The authors want to thank the Eukaryotic Single-Cell Genomics facility (Stockholm, Sweden) and in particular Henrik Gezelius and Anastasios Glaros for excellent sequencing services and customer support. MEK was supported by the Novo Nordisk Foundation (Postdoc fellowship in Endocrinology and Metabolism at International Elite Environments, NNF17OC0026874) and Stiftelsen Riksbankens Jubileumsfond (Erik Rönnbergs fond stipend). LF was supported by Austrian Science Fund DOC 33-B27. T.G.B. was supported by a Lise Meitner grant from the Austrian Science Fund (M2688-B28). TS was supported by NIH grant DE027568 to MB. SH is supported by Swedish Research Council, Brain Foundation and StratNeuro. VD was supported by the Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075-15-2022-301). TP was supported by the Swedish Research Council (2020-00884); Knut and Alice Wallenberg's Foundation and Söderberg's Foundation. IA was supported by Paradifference Foundation, The Swedish Cancer Society, Bertil Hållsten Research Foundation, Swedish Research Council, ERC Consolidator and EMBO Young Investigator Grants. Author contributions: Maria Eleni Kastriti: Conceptualization; data curation; formal analysis; supervision; validation; investigation; visualization; writing – original draft; project administration; writing – review and editing. Louis Faure: Resources; data curation; software; formal analysis; investigation; visualization; methodology; writing – original draft; writing – review and editing. Dorothea Von Ahsen: Formal analysis; validation; investigation; visualization; methodology. Johan Boström: Resources; investigation; writing – review and editing. Thibault Gerald Bouderlique: Validation; investigation; visualization; writing – review and editing. Tatiana Solovieva: Data curation; formal analysis; investigation; visualization; methodology; writing – review and editing. Cameron Jackson: Investigation. Marianne Bronner: Resources; supervision; funding acquisition; methodology; writing – review and editing. Dies Meijer: Writing – review and editing. Saida Hadjab: Resources; funding acquisition; writing – review and editing. Francois Lallemend: Resources; funding acquisition; writing – review and editing. Alek Erickson: Resources; writing – original draft. Marketa Kaucka: Resources; writing – review and editing. Viacheslav Dyachuk: Resources; writing – review and editing. Thomas Perlmann: Resources; writing – review and editing. Laura Lahti: Resources; writing – review and editing. Jan Krivanek: Resources; investigation; writing – review and editing. Jean-Francois Brunet: Resources; writing – review and editing. Kaj Fried: Writing – review and editing. Igor Adameyko: Conceptualization; supervision; funding acquisition; writing – original draft; project administration; writing – review and editing. Data availability: Newly generated single-cell transcriptomic data and previously published data sets have been uploaded under GSE201257 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE201257). Two pagoda2 web applications are available on the following link: https://adameykolab.srv.meduniwien.ac.at/glia_gene_umap/ with the (gene-based embedding, and https://adameykolab.srv.meduniwien.ac.at/glia_scenic_umap/ with (SCENIC-based UMAP embedding). Cropped images used for quantification of the "hub" markers Itga4, Serpine2 and Sox8 following RNAscope® in situ hybridization can be found at DOI 10.6084/m9.figshare.19620102. Code and data for downstream analysis are found on the following repository: https://github.com/LouisFaure/glialfates_paper. The authors declare that they have no conflict of interest.

Attached Files

Supplemental Material - embj2021108780-sup-0001-appendix.pdf

Supplemental Material - embj2021108780-sup-0002-evfigs.pdf

Supplemental Material - embj2021108780-sup-0003-datasetev1.pdf

In Press - The_EMBO_Journal_-_2022_-_Kastriti_-_Schwann_cell_precursors_represent_a_neural_crest‐like_state_with_biased_multipotency.pdf

Files

The_EMBO_Journal_-_2022_-_Kastriti_-_Schwann_cell_precursors_represent_a_neural_crest‐like_state_with_biased_multipotency.pdf

Additional details

Created:
August 22, 2023
Modified:
December 22, 2023