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, Kurbel V, Parmar A, Sharma G, Karandasheva K, Abuhattum S, Lyraki O, Beck T, Mueller P, Schlüßler R, Frischknecht R, Wehner A, Krombholz N, Steigenberger B, Beis D, Takeoka A, Blümcke I, Möllmert S, Singh K, Guck J, Kobow K, Wehner D (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 14

Article Number: 6814

Issue: 1

DOI: 10.1038/s41467-023-42339-7

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.

Authors with CRIS profile

Julia Kolb Lehrstuhl für Tierphysiologie Nora John Lehrstuhl für Tierphysiologie Conrad Möckel Lehrstuhl für Biologische Optomechanik Olga Lyraki Lehrstuhl für Tierphysiologie Renato Frischknecht Lehrstuhl für Tierphysiologie Ingmar Blümcke Lehrstuhl für Neuropathologie Stephanie Möllmert
Jochen Guck Lehrstuhl für Biologische Optomechanik Katja Kobow Institute of Neuropathology

Additional Organisation(s)

Sonderforschungsbereich 1540: Erforschung der Mechanik des Gehirns (EBM): Verständnis, Engineering und Nutzung mechanischer Eigenschaften und Signale in der Entwicklung, Physiologie und Pathologie des zentralen Nervensystems

Involved external institutions

Max-Planck-Institut für die Physik des Lichts (MPL) / Max Planck Institute for the Science of Light DE Germany (DE) Academy of Athens / Ακαδημία Αθηνών GR Greece (GR) Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry DE Germany (DE) Technische Universität Dresden DE Germany (DE) Neuro-Electronics Research Flanders (NERF) BE Belgium (BE)

How to cite

APA:

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

MLA:

Kolb, Julia, et al. "Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment." Nature Communications 14 (2023).

BibTeX: Download