Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by a massive immune cell infiltrate, tissue destruction and extensive fibrosis. We aimed to elucidate the role of fibroblasts in the pathophysiology of HS. Single-cell RNA-sequencing was performed on chronic lesional skin samples of 8 HS patients and skin samples of 8 controls. Ex vivo experiments were performed on primary dermal fibroblasts from chronic HS lesions (n=3). Fibroblast subclustering revealed 6 subsets (SFRP2+, COL11A+, SFRP4+, LSP1+, RAMP1+, and CXCL13+). Two of these, SFRP4+ and CXCL13+, were specifically derived from HS samples. The SFRP4+ subset was identified as myofibroblasts and displayed prominent pro-fibrotic characteristics. Development and activation of this subset was found to be driven by key HS-associated inflammatory cytokines (IFNγ, IL-1β, and TNF). Analysis of the expression of transcription factors within the SFRP4+ subset identified several upregulated components of the Hippo pathway (YAP, WWTR1, TEAD1-4). To determine the functional relevance of the Hippo pathway in HS fibroblasts, primary dermal fibroblasts were stimulated with TRULI (promoting the Hippo pathway) and verteporfin (inhibiting the Hippo pathway). Treatment with TRULI led to a significant increase in pro-fibrotic markers in HS fibroblasts (ACTA2 and COL1A1) on both mRNA and protein level and enhanced proliferation of HS fibroblasts. Verteporfin treatment elicited opposite results and downregulated pro-fibrotic markers, proliferation, and migration. Overall, these results identify a central role for the Hippo pathway in promoting myofibroblast activation in HS and provides pre-clinical evidence that modulation of the Hippo pathway can reverse the pro-fibrotic phenotypes of myofibroblasts in HS.

ESDR594 - Hippo pathway drives excessive fibrosis in Hidradenitis Suppurativa

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.