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+ fibroblast state with an inflammation-associated, less differentiated, non-fibrotic profile. Ca2+-dependent induction of this fibroblast state precedes and is critical for the initiation of the inflammatory response. Subsequently, cthrc1a+ 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.