Clinically and biologically inspired strategies to alleviate skin fibrosis

Abstract

Fibrotic diseases constitute a major health problem worldwide owing to the large number of affected individuals and a lack of effective disease-modifying therapeutic solutions. It is therefore clear that new biological insights and engineering strategies are needed to address this daunting unmet medical need. In this PhD study, I present two novel approaches to alleviate fibrosis, focusing on skin scarring as a model tissue. The first approach is inspired by the laxity paradox, a clinical observation made in patients undergoing hair transplantation. This phenomenon describes formation of wide stretched scars in patients with very loose scalp skin and low skin tension, an observation that is in contrary to the previously established and generally accepted link between an increased skin tension and extensive scarring. I have decided to explore the mechanism of the low-tension scarring and identified downregulation of the expression of thrombospondin 1 and 2 in dermal fibroblasts isolated from the scar as a possible contributing factor. The second approach was inspired by how healthy hair-bearing skin undergoes physiological remodelling during the regular hair follicle cycle. In a pilot clinical study in collaboration with a hair transplantation clinic, we tested if anagen hair follicles transplanted into human scars can actively remodel fibrotic tissue, similar to how they remodel the healthy skin. I tested the fibrotic tissue before and after hair transplantation and found a shift in the morphology and transcriptional profile towards the healthy phenotype. I expect the results of this thesis to inspire further research into both the role of thrombospondins in low-tension scarring and the observation of hair follicle-induced scar remodelling. Long term, increased understanding of the mechanisms behind scar formation and complex interactions between cells in the fibrotic environment could contribute to the design of novel therapeutic strategies to achieve the holy grail of scarless skin regeneration.