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

Julia Kolb, Vasiliki Tsata, Nora John, Kyoohyun Kim, Conrad Möckel, Gonzalo Rosso, Veronika Kurbel, Asha Parmar, Gargi Sharma, Kristina Karandasheva, Shada Abuhattum, Olga Lyraki, Timon Beck, Paul Müller, Raimund Schlüßler, Renato Frischknecht, Anja Wehner, Nicole Krombholz, Barbara Steigenberger, Dimitris Beis, Aya Takeoka, Ingmar Blümcke, Stephanie Möllmert, Kanwarpal Singh, Jochen Guck, Katja Kobow and Daniel Wehner ()
Additional contact information
Julia Kolb: Max Planck Institute for the Science of Light
Vasiliki Tsata: Biomedical Research Foundation Academy of Athens
Nora John: Max Planck Institute for the Science of Light
Kyoohyun Kim: Max Planck Institute for the Science of Light
Conrad Möckel: Max Planck Institute for the Science of Light
Gonzalo Rosso: Max Planck Institute for the Science of Light
Veronika Kurbel: Friedrich-Alexander-University Erlangen-Nürnberg
Asha Parmar: Max Planck Institute for the Science of Light
Gargi Sharma: Max Planck Institute for the Science of Light
Kristina Karandasheva: Friedrich-Alexander-University Erlangen-Nürnberg
Shada Abuhattum: Max Planck Institute for the Science of Light
Olga Lyraki: Max Planck Institute for the Science of Light
Timon Beck: Max Planck Institute for the Science of Light
Paul Müller: Max Planck Institute for the Science of Light
Raimund Schlüßler: Technische Universität Dresden
Renato Frischknecht: Friedrich-Alexander-University Erlangen-Nürnberg
Anja Wehner: Max Planck Institute of Biochemistry
Nicole Krombholz: Max Planck Institute of Biochemistry
Barbara Steigenberger: Max Planck Institute of Biochemistry
Dimitris Beis: Biomedical Research Foundation Academy of Athens
Aya Takeoka: VIB-Neuroelectronics Research Flanders
Ingmar Blümcke: Friedrich-Alexander-University Erlangen-Nürnberg
Stephanie Möllmert: Max Planck Institute for the Science of Light
Kanwarpal Singh: Max Planck Institute for the Science of Light
Jochen Guck: Max Planck Institute for the Science of Light
Katja Kobow: Friedrich-Alexander-University Erlangen-Nürnberg
Daniel Wehner: Max Planck Institute for the Science of Light

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42339-7

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