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

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Kolb, Julia
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Wehner Research Group, Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;
Friedrich-Alexander-Universität Erlangen-Nürnberg;
Wehner Research Group, Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons268904

John, Nora
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Wehner Research Group, Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;
Friedrich-Alexander-Universität Erlangen-Nürnberg;
Wehner Research Group, Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons256228

Kim, Kyoohyun
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons255614

Möckel, Conrad
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;
Friedrich-Alexander-Universität Erlangen-Nürnberg;

Rosso, Gonzalo
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons260806

Parmar, Asha
Singh Research Group, Research Groups, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons245528

Sharma, Gargi
Singh Research Group, Research Groups, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons247999

Abuhattum Hofemeier, Shada
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;

Lyraki, Olga
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;
Friedrich-Alexander-Universität Erlangen-Nürnberg;

/persons/resource/persons256075

Beck, Timon
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons248158

Müller, Paul
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons255608

Möllmert, Stephanie
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons241409

Singh, Kanwarpal
Singh Research Group, Research Groups, Max Planck Institute for the Science of Light, Max Planck Society;

/persons/resource/persons241284

Guck, Jochen
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;
Friedrich-Alexander-Universität Erlangen-Nürnberg;

/persons/resource/persons255618

Wehner, Daniel
Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Wehner Research Group, Guck Division, Max Planck Institute for the Science of Light, Max Planck Society;
Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;
Wehner Research Group, Guck Division, Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society;

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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-000D-E0CE-E

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.