1473 Hippo pathway drives excessive fibrosis in hidradenitis suppurativa

Hidradenitis suppurativa(HS) is a chronic skin disease characterized by a massive immune cell infiltrate, tissue destruction and extensive fibrosis. We aimed to elucidate the role of fibroblasts(FBs) in the pathophysiology of HS. We performed single cell RNA-seq on chronic lesional skin of 5 HS patients and skin of 7 controls.Ex vivo experiments were performed on primary dermal FBs from chronic HS lesions (n=5). FB subclustering revealed 6 subsets; SFRP2+, COL11A+, SFRP4+, LSP1+, RAMP1+, and CXCL13+. The SFRP4+ and CXCL13+ subsets were specifically derived from HS samples. The SFRP4+ subset displayed prominent pro-fibrotic characteristics and was identified as myofibroblasts. Development and activation of this subset was found to be driven by TGFB and key HS cytokines; TNF, IL1B, and IFNG. Moreover, this subset showed increased expression of Hippo pathway transcription factors and coactivators; YAP1, WWTR1, and TEAD1-4. To determine the functional relevance of this pathway in HS, primary dermal HS FBs were stimulated with TRULI (promoting) and verteporfin (VP, inhibiting the pathway). VP significantly reduced protein and RNA expression of collagen I and to a lesser extent smooth muscle actin in HS FBs. VP also significantly inhibited HS FB contractility and resulted in a significant dose-dependent reduction of proliferation and migration. TRULI treatment resulted in a non-significant increased RNA expression of smooth muscle actin and collagen I. Treatment with TRULI significantly increased proliferation but failed to increase migration or gel contraction. 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 phenotype of HS myofibroblasts.