Is the future scarless? – Fibroblasts as targets for scarless wound healing: a narrative review

Introduction: Scarless healing is the ideal outcome of wound healing and is exhibited in some species. This narrative review assembles the current understanding of fibroblast heterogenicity along with the latest fibroblast-related targets for scar reduction therapies. Human regenerative wound healing is deemed possible due to the wound regeneration already seen in the early gestation foetus. Methods: This literature narrative review was undertaken by searching PubMed and Web of Science databases and Google Scholar to find articles concerning the fibroblast involvement in wound healing. We evaluated and collated these articles to form a consensus of the current understanding of the field. Discussion: This article describes current understanding of fibroblast heterogenicity and involvement in wound healing, focusing on the role of fibroblasts during physiological scarring. We also present the current most promising targets involving fibroblasts in the reduction of scarring and how we can manipulate the behaviour of fibroblasts to mimic the wound regeneration models in the human foetus. These targets include the pro-fibrotic EN1 positive fibroblast lineage, TGFβ1 inhibition, and genetic therapies utilising miRNAs and siRNAs. Conclusion: No therapies are currently available to eradicate scarring; however, treatment options are available to reduce the appearance of scarring. Further research into the heterogenicity and interactions of fibroblasts in both the foetus and adult is needed, and this may lead to the development of novel treatments against scarring. Lay Summary Scarless healing refers to the repair of a wound with minimal residual scarring. The main cell responsible for the repair process is the fibroblast. It is now understood that there are different types of fibroblasts. Simply, some of these fibroblasts lead to scarring and some lead to regeneration. The early human foetus has mainly regenerative fibroblasts, but during aging the number of scarring fibroblasts increase to become the majority in the adult . Understanding how we can modify this process may ultimately result in the reduction in scarring. Currently, scar reduction therapies are aimed at optimal wound healing, surgical removal of abnormal scars, and using steroids and other drugs to encourage better wound repair by limiting the effect of scarring fibroblasts. Future therapies aim to target specific groups of fibroblasts to encourage regenerative wound healing. This narrative review aims to cover the current understanding of the different groups of fibroblasts and their effect on wound healing. We also cover the current and potential therapies that can be used to reduce scarring and suggest further areas for research in this field.