Keloid scars, which are excessive forms of cutaneous scarring, overgrow the boundaries of the original wound and do not regress spontaneously. Although keloid pathogenesis has been linked to numerous dysregulated signalling pathways, the underlying causes remain poorly understood. Keloid scars have been shown to be 10-50 times stiffer than normal skin and often form in areas of the body where skin tension is high. As a result, it is thought that the formation of keloid scars may be influenced by mechanical forces. The aim of this study was to investigate the direct effects of tissue stiffness on the behaviour of normal (NDF) and keloid dermal fibroblasts (KDF) and explore the potential crosstalk with signalling pathways. To investigate the response to extracellular matrix (ECM) stiffness both NDFs and KDFs were cultured on collagen-coated polyacrylamide (PA) hydrogels mimicking the stiffness of normal (8kPa) and keloid skin (70-214kPa). KDFs became more spread on the stiff substrates compared to soft with increased focal adhesions and F-actin stress fibres, changes not observed within NDFs. Pathway analysis of RNA-sequencing data identified autophagy as a mechanosensitive pathway that is dysregulated in KDFs. Follow-up investigations showed increased LC3-II (a key autophagy regulator) protein levels in both KDFs and NDFs when grown on stiff PA hydrogels compared to soft. Additionally, preliminary experiments indicated that autophagic flux is intact in NDFs but impaired in KDFs, and this response was sensitive to treatment with the myosin-II inhibitor, blebbistatin, demonstrating the importance of F-actin tension in the process of autophagy. In conclusion, this project has shown that KDFs are more mechano-responsive to ECM stiffness than NDFs and that autophagy is a mechanically sensitive pathway that is altered in KDFs. These findings have revealed a novel biomechanical-autophagy signalling axis that may contribute to the pathogenesis of keloid scars, and on-going studies aim to elucidate the functional role of this mechanism in ECM deposition and scar formation.

ESDR597 - Altered mechano-sensing and autophagy in keloid dermal fibroblasts

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.