Biphasic inflammation control by dedifferentiated fibroblasts enables axon regeneration after spinal cord injury in zebrafish

John N, Fleming T, Kolb J, Lyraki O, Vásquez Sepúlveda SI, Parmar A, Kim K, Tarczewska M, Singh K, Marini F, Singh SP, Falk S, Franze K, Guck J, Wehner D (2025)

Publication Status: Submitted

Publication Type: Unpublished / Preprint

Future Publication Type: Journal article

Publication year: 2025

DOI: 10.1101/2025.01.27.635043

Abstract

Fibrosis and persistent inflammation are interconnected processes that inhibit axon regeneration in the mammalian central nervous system (CNS). In zebrafish, by contrast, fibroblast-derived extracellular matrix deposition and inflammation are tightly regulated to facilitate regeneration. However, the regulatory cross-talk between fibroblasts and the innate immune system in the regenerating CNS remains poorly understood. Here, we show that zebrafish fibroblasts possess a dual role in inducing and resolving inflammation, which are both essential for regeneration. We identify a transient, injury-specific cthrc1a+ fibroblast state with an inflammation-associated, less differentiated, and non-fibrotic profile. Induction of this fibroblast state precedes and contributes to the initiation of the inflammatory response. At the peak of neutrophil influx, cthrc1a+ fibroblasts coordinate the resolution of inflammation. Disruption of these inflammation dynamics alters the mechano-structural properties of the lesion environment and inhibits axon regeneration. This establishes the biphasic inflammation control by dedifferentiated fibroblasts as a pivotal mechanism for CNS regeneration.

Authors with CRIS profile

Nora John Lehrstuhl für Tierphysiologie Julia Kolb Lehrstuhl für Tierphysiologie Olga Lyraki Lehrstuhl für Tierphysiologie Sebastián Ignacio Vásquez Sepúlveda Lehrstuhl für Medizinische Physik und Mikrogewebetechnik (IMP) Maria Tarczewska Lehrstuhl für Medizinische Physik und Mikrogewebetechnik (IMP) Sven Falk Lehrstuhl für Biochemie und Pathobiochemie Kristian Franze Lehrstuhl für Medizinische Physik und Mikrogewebetechnik (IMP) Jochen Guck Lehrstuhl für Biologische Optomechanik

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) Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE) Université libre de Bruxelles (ULB) / Free University of Brussels BE Belgium (BE)

How to cite

APA:

John, N., Fleming, T., Kolb, J., Lyraki, O., Vásquez Sepúlveda, S.I., Parmar, A.,... Wehner, D. (2025). Biphasic inflammation control by dedifferentiated fibroblasts enables axon regeneration after spinal cord injury in zebrafish. (Unpublished, Submitted).

MLA:

John, Nora, et al. Biphasic inflammation control by dedifferentiated fibroblasts enables axon regeneration after spinal cord injury in zebrafish. Unpublished, Submitted. 2025.

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