Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the 
structural and mechanical properties of the lesion environment

Kolb, Julia; Tsata, Vasiliki; John, Nora; Kim, Kyoohyun; Möckel, Conrad; Rosso, Gonzalo; Kurbel, Veronika; Parmar, Asha; Sharma, Gargi; Karandasheva, Kristina; Abuhattum Hofemeier, Shada; Lyraki, Olga; Beck, Timon; Müller, Paul; Schlüßler, Raimund; Frischknecht, Renato; Wehner, Anja; Krombholz, Nicole; Steigenberger, Barbara; Beis, Dimitris; Takeoka, Aya; Blümcke, Ingmar; Möllmert, Stephanie; Singh, Kanwarpal; Guck, Jochen; Kobow, Katja; Wehner, Daniel

doi:10.1038/s41467-023-42339-7

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Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment

Kolb, J., Tsata, V., John, N., Kim, K., Möckel, C., Rosso, G., et al. (2023). Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment. Nature Communications, 14: 6814. doi:10.1038/s41467-023-42339-7.

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2023

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Kolb, Julia^{1, 2, 3, 4}, Author
Tsata, Vasiliki⁵, Author
John, Nora^{1, 2, 3, 4}, Author
Kim, Kyoohyun^{1, 3}, Author
Möckel, Conrad^{1, 3, 4}, Author
Rosso, Gonzalo^{1, 3}, Author
Kurbel, Veronika⁵, Author
Parmar, Asha⁶, Author
Sharma, Gargi⁶, Author
Karandasheva, Kristina⁵, Author
Abuhattum Hofemeier, Shada^{1, 3}, Author
Lyraki, Olga^{1, 3, 4}, Author
Beck, Timon^{1, 3}, Author
Müller, Paul^{1, 3}, Author
Schlüßler, Raimund⁵, Author
Frischknecht, Renato⁵, Author
Wehner, Anja⁵, Author
Krombholz, Nicole⁵, Author
Steigenberger, Barbara⁵, Author
Beis, Dimitris⁵, Author
Takeoka, Aya⁵, AuthorBlümcke, Ingmar⁵, AuthorMöllmert, Stephanie^{1, 3}, Author         Singh, Kanwarpal⁶, Author         Guck, Jochen^{1, 3, 4}, Author         Kobow, Katja⁵, AuthorWehner, Daniel^{1, 2, 3}, Author          more..

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1Guck Division, Max Planck Institute for the Science of Light, Max Planck Society, ou_3164416
2Wehner Research Group, Guck Division, Max Planck Institute for the Science of Light, Max Planck Society, ou_3358768
3Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society, ou_3164414
4Friedrich-Alexander-Universität Erlangen-Nürnberg, ou_persistent22
5external, ou_persistent22
6Singh Research Group, Research Groups, Max Planck Institute for the Science of Light, Max Planck Society, ou_3164411

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Abstract: Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a contributing factor to regeneration failure in mammals. We demonstrate that the SLRPs chondroadherin, fibromodulin, lumican, and prolargin are enriched in rodent and human but not zebrafish CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer mechano-structural properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as inhibitory ECM factors that impair axon regeneration by modifying tissue mechanics and structure, and identifies their enrichment as a feature of human brain and spinal cord lesions. These findings imply that SLRPs may be targets for therapeutic strategies to promote CNS regeneration.

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Language(s): eng - English

Dates: Published Online: 2023-10-26

Publication Status: Published online

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Table of Contents: Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a contributing factor to regeneration failure in mammals. We demonstrate that the SLRPs chondroadherin, fibromodulin, lumican, and prolargin are enriched in rodent and human but not zebrafish CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer mechano-structural properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as inhibitory ECM factors that impair axon regeneration by modifying tissue mechanics and structure, and identifies their enrichment as a feature of human brain and spinal cord lesions. These findings imply that SLRPs may be targets for therapeutic strategies to promote CNS regeneration.

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Identifiers: DOI: 10.1038/s41467-023-42339-7

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Title: Nature Communications

Abbreviation : Nat. Commun.

Source Genre: Journal

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Publ. Info: London : Nature Publishing Group

Pages: - Volume / Issue: 14 Sequence Number: 6814 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723