Targeting Fibroblasts to Enable Scarless Healing

Regeneration without scarring is a desirable goal. Given that this ability exists in very early life in mammals, is retained in limited ways into adulthood in some mammalian species, and is exhibited in a range of other higher animals such as salamanders, it seems plausible that enabling regeneration without scarring is just a matter of finding the right switches to change cell behavior. That search has been ongoing in earnest for several decades now, digging into the biology of highly regenerative species, while manipulating the biology of mammals in search of the key, the most important points of intervention.

Fibroblasts are mesenchymal cells that account for the majority of the cellular density of the dermis and have a crucial role in wound healing. Until recently, fibroblasts were not considered to have extensive involvement in the field of scarless wound healing and were seen only as extracellular matrix (ECM) producing cells. It is now understood that there are many lineages of human fibroblasts with distinct and heterogeneous functions. 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.

Scarring is the typical physiological outcome of wound healing. It is an evolutionary adaptation that provides quick and effective repair to damaged tissues, sometimes at the expense of tissue integrity and function. Scar tissue lacks skin appendages and has an organised collagen structure replacing the typical "basket-weave" dermal structure in unwounded tissues, leading to reduced tensile strength. Ideal wound repair would involve regeneration of the normal skin structure, including its associated appendages.

The ability to prevent scarring has applications beyond cosmetic and aesthetic uses, with the ability to restore function to extensively damaged tissues and preclude pathological scarring. 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.


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