The Molecular & Cellular Interactions of Wound-Induced Hydrogen Peroxide in the Regenerating Larval Zebrafish Tail

The ability of humans to heal from wounding is fairly limited; whilst certain organs such as the blood and skin have an in-built capacity for homeostatic regeneration to maintain physiological function, we are generally poor at reparative regeneration following injury. Zebrafish, however, have a much greater capacity for healing and are able to restore both form and function in multiple organs when damaged. This trait is shared between multiple species and relies on the reactivation of conserved developmental pathways. The precise interactions that determine whether a wound regenerates or not are currently not clear, and more work must be done to understand the molecular and cellular interactions which mediate the regenerative response. This could identify the limiting steps in our own wound-healing processes that we are able to manipulate in order to induce regeneration and improve clinical outcomes and quality of life for millions of patients including amputees, paralysed trauma victims, and sufferers of stroke or heart failure. Here, I present evidence that wound-induced hydrogen peroxide (H₂O₂) is required for the initiation of regeneration in the larval zebrafish tail via the activation of the Hedgehog (Hh), and subsequently the Wnt and FGF pathways. H₂O₂ induces activation of SFKs in the epithelial cells at the wound margin which trigger the extrusion of the severed notochord following tail amputation. This physical extrusion is necessary to induce upregulation of the Hh ligands Shh and Ihh in the notochord cells which stimulates Hh pathway activation in the surrounding tissue in a paracrine fashion, acting as a redox-sensitive central organiser. This pro-regenerative effect of H₂O₂ appears to be independent of its role as a pro-inflammatory signal, and shows that H₂O₂ exerts control over multiple parallel wound responses. Continued work will be required to characterise the full extent of regulatory control that this promiscuous wound signal possesses.