Morphogen and epigenetic regulation of wound healing

Abstract

Events during wound repair are reminiscent of developmental events such as cell migration, redifferentiation and proliferation. Factors controlling these processes in the early embryo may therefore be important regulators in adult wound healing. Fibrosis is a disease of dysregulated wound healing with fibroproliferative disorders accounting for 45% of deaths in developed nations. Despite this, effective antifibrotic therapy is limited. Understanding factors regulating wound repair process will aid identification of potential therapeutic targets. This project first explored how activation of developmental signalling pathways influences regulation of myofibroblast transdifferentiation and behaviour in liver fibrosis, focusing on the Wnt signalling pathway. Wnt signalling was upregulated in activated myofibroblasts, with significantly increased expression of non-canonical ligands. Wnt stimulus did not provoke a canonical/β-Catenin mediated response, with myofibroblasts responding through non-canonical associated signalling instead. Inhibition of Wnt signalling reduced classic markers of fibrosis, suggesting a profibrotic role for Wnt signalling during liver fibrosis. Stimulus with the non-canonical ligand Wnt5a did not directly affect expression of fibrotic markers in myofibroblasts. Instead it appeared to act as a prosurvival factor and increased expression of profibrotic cytokines in resident liver macrophages. Dynamic changes in DNA methylation pattern also regulate embryonic development. This project next explored whether inheritance of epigenetic marks could alter early DNA methylation patterns and affect response to injury in adult, focusing on the histone variant H2A.Z. H2A.Z is thought anti-correlative to DNA methylation and has been shown to be enriched in the sperm of injured animals in a model of transgenerational adaptation to wound healing. H2A.Z expression was depleted via morpholino injection in early zebrafish embryos, resulting in significant mortality and phenotypic abnormality. Injected animals displayed significant hypermethylation of DNA during early embryonic periods. This suggests that alteration of epigenetic marks can influence methylation status of DNA.