Biphasic inflammation control by fibroblasts enables spinal cord regeneration in zebrafish
Fibrosis and persistent inflammation are interconnected processes that inhibit axon regeneration in the mammalian central nervous system (CNS). Here, we show that in zebrafish, the interplay between fibroblasts and immune cells is required for regeneration. Using temporally resolved single-cell transcriptomics, we identify a transient, injury-induced cthrc1a<sup>+</sup> fibroblast state with an inflammation-associated, less differentiated, non-fibrotic profile. Ca<sup>2+</sup>-dependent induction of this fibroblast state precedes and is critical for the initiation of the inflammatory response. Subsequently, cthrc1a<sup>+</sup> fibroblasts coordinate the resolution of the neutrophil-driven inflammation. Disruption of these inflammation dynamics alters the mechano-structural properties of the lesion microenvironment and inhibits regeneration and recovery of locomotor function. Thus, zebrafish fibroblasts possess a dual role in inducing and resolving inflammation, which are both required for regeneration. This establishes the biphasic inflammation control by fibroblasts as an important mechanism directing CNS regeneration.
Authors
- Julia Kolb (ORCID: https://orcid.org/0000-0003-2767-4905)
- Kristian Franze (ORCID: https://orcid.org/0000-0002-8425-7297)
- Daniel Wehner (ORCID: https://orcid.org/0000-0003-2880-4759)
- Kyoohyun Kim (ORCID: https://orcid.org/0000-0003-1808-775X)
- Asha Parmar (ORCID: https://orcid.org/0000-0002-5630-9483)
- Sven Falk (ORCID: https://orcid.org/0000-0003-4194-9274)
- Jochen Guck (ORCID: https://orcid.org/0000-0002-1453-6119)
- Vasiliki Tsata (ORCID: https://orcid.org/0000-0002-7741-9702)
- Nora John (ORCID: https://orcid.org/0000-0002-4428-9083)
- Pooja Gupta (ORCID: https://orcid.org/0000-0001-9078-255X)
- Thomas Henry Fleming (ORCID: https://orcid.org/0000-0002-3232-4515)
- Sumeet Pal Singh (ORCID: https://orcid.org/0000-0002-5154-3318)
- Fédérico Marini (ORCID: https://orcid.org/0000-0003-3252-7758)
- Kanwarpal Singh (ORCID: https://orcid.org/0000-0002-6884-8089)
- Sebastián Vásquez-Sepúlveda
- Olga Lyraki
- Maria Tarczewska
Institutions
- Université Libre de Bruxelles (BE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Johannes Gutenberg University Mainz (DE)
- Academy of Athens (GR)
- Universitätsklinikum Erlangen (DE)
- Biomedical Research Foundation of the Academy of Athens (GR)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Max Planck Institute for the Science of Light (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-10-23
- DOI
- https://doi.org/10.1016/j.celrep.2025.116469
- Citations
- 4
- Primary Topic
- Zebrafish Biomedical Research Applications
- Type
- article
- Field-Weighted Citation Impact
- 4.61