565 A novel role for the ETS family transcription factor ERG in hypertrophic scarring

Abstract

A hypertrophic scar is characterized by excessive collagen deposition which gives rise to a raised scar, but not to the degree observed with keloids. Like keloids, they often form at the sites of cuts and burns and as a result of surgery. The investigation of pathological scarring is frequently undermined by a lack of site-matched tissue, as well as the use of different control and test subjects. To eliminate this problem, we examined skin from 30 patients undergoing two-stage surgical ear reconstruction, a procedure that requires sequential incisions in the same body site to harvest cartilage, providing a unique model of site-matched, age-matched, internally controlled unscarred skin and subsequent scar tissue. Crucially this allows us to find predictive markers of hypertrophic scarring in unscarred normal skin Comparison of cultured dermal fibroblasts from the unscarred skin of individuals who go on the scar hypertrophically (n=7) vs. those who go on to scar normally (n=23), showed no significant differences in proliferation or motility or expression of key wound healing or TGFβ signalling proteins previously implicated in hypertrophic scarring. RNAseq analysis indicated that fibroblasts from skin that hypertrophically scars had a distinct gene expression signature, with expression levels of the pro-angiogenic transcription factor ERG, correlating with scar severity. These initial changes significantly altered the dermal environment in the hypertrophic scar. The resulting hypertrophic and normtrophic scars were analysed after 6 months by label-free mass spectrometry. We identified signficantly decreased levels of the key scar remodelling-associated protein arginase in hypertrophic scars, reflecting loss of arginase-expressing cells that are required for scar remodelling. We show here that the RNAseq analysis and mass spectometric investigations using this novel surgery model, are complementary approachs to find novel markers of hypertrophic scarring and potentially novel therapies.