A critical factor for the lack of axonal regrowth after spinal cord injury in mammals is the formation of scar tissue in the lesion site, which constitutes a hostile environment for axon growth. The composition of the scar is complex, consisting of different compartments with distinct cellular and molecular signature. The fibrous component of the scar in the lesion center forms through invading non-neural cells, most-prominently fibroblasts of perivascular origin, which deposit a dense meshwork of collagen-rich extracellular matrix (ECM). Although, our understanding about regulation and composition is limited and different concepts exist of how the lesion ECM interferes with axonal regrowth, the excess deposition of ECM molecules is considered a major barrier to axon growth.
In contrast to mammals, a spinal lesion site in zebrafish is permissive for axon growth. Understanding how the lesion site is conditioned to permit axon regeneration in zebrafish may have therapeutic relevance for non-regenerating mammals. Our previous work showed that in strong contrast to mammals, fibroblasts in zebrafish promote axon regeneration by depositing a growth-permissive ECM in the lesion site (Wehner, 2017. Nature Commun). We found that spinal cord injury triggers upregulation of Wnt signaling in fibroblasts accumulating in the lesion site. Wnt signaling regulates col12a1 transcription and deposition of collagen XII by fibroblasts in the lesion ECM. Functional experiments showed that collagen XII is required and sufficient for axonal regrowth across the lesion site. Our findings indicate that in a regeneration-competent vertebrate ECM deposition by fibroblasts is critical for establishing an axon growth-permissive lesion environment and identified collagen XII as promoter of axonal regeneration. Projects in the lab are currently focussing on:
defining the pro-regenerative fibroblast response after spinal cord injury in zebrafish, to understand how the injury response might differ from their scar-forming mammalian counterparts;
identifying novel fibroblast-derived ECM molecules that promote axonal regrowth across the zebrafish lesion site and unravelling how the lesion ECM promotes regeneration;
characterising the mechanical properties of the regeneration-permissive lesion site in zebrafish as well as exploring how fibroblasts and ECM molecules determine their properties.