Flightless I is a key regulator of the fibroproliferative process in hypertrophic scarring and a target for a novel antiscarring therapy

Summary Background Hypertrophic scarring carries a large burden of disease, including disfigurement, pain and disability. There is currently no effective medical treatment to reduce or prevent hypertrophic scarring. Flightless I (Flii), a member of the gelsolin family of actin remodelling proteins, is an important negative regulator of wound repair. Objectives The objective of this study was to investigate the role of Flii as a potential regulator of hypertrophic scarring. Methods Using human skin samples and an animal model of bleomycin‐induced hypertrophic scarring in mice that overexpress or have reduced expression of Flii, we investigated its effect on dermal fibrosis and hypertrophic scarring. Results Flii expression was increased in human burns and hypertrophic scars. A similar increase in Flii was observed in hypertrophic scars formed in mice post‐treatment with bleomycin. However, Flii‐deficient (Flii+/−) mice had reduced scarring in response to bleomycin evidenced by decreased dermal thickness, smaller cross‐sectional scar areas, fewer myofibroblasts and a decreased collagen I/III ratio. In contrast, bleomycin‐treated Flii‐overexpressing mice (FliiTg/Tg) showed increased scar dermal thickness, larger cross‐sectional scar areas, more myofibroblasts and an increased collagen I/III ratio. Injecting developing scars with a Flii neutralizing antibody led to a significant reduction in the size of the scars and a reduction in the collagen I/III ratio. Conclusions This study identifies Flii as a profibrotic agent that contributes to excessive scar formation. Reducing its activity using neutralizing antibodies is a promising approach for reducing hypertrophic scarring. What's already known about this topic? Flightless I (Flii) adversely affects wound healing by inhibiting migration, proliferation and adhesion. Increased Flii in transgenic mice models impairs re‐epithelialization and in a burn model leads to increased deposition of collagen and profibrotic growth factors. What does this study add? Flii is elevated in human hypertrophic scars and reducing its level in a mouse model of hypertrophic scarring either genetically or by using an Flii neutralizing antibody decreases the severity of fibrosis and scarring. Plain language summary available online