Abstract
Fibrosis is perpetuated by an autocrine, pro-adhesive signaling loop maintained by the synthetic and contractile abilities of myofibroblasts and the stiff, highly-crosslinked extracellular matrix. Transcriptional complexes that are exquisitely responsive to mechanotransduction include the co-activator YAP1, which regulates the expression of members of the CCN family of matricellular proteins such as CCN2 and CCN1. Although selective YAP1 inhibitors exist, the effect of these inhibitors on profibrotic gene expression in fibroblasts is largely unknown, and is the subject of our current study. Herein, we use genome-wide expression profiling, real-time polymerase chain reaction and Western blot analyses, cell migration and collagen gel contraction assays to assess the ability of a selective YAP inhibitor verteporfin (VP) to block fibrogenic activities in dermal fibroblasts from healthy individual human controls and those from isolated from fibrotic lesions of patients with diffuse cutaneous systemic sclerosis (dcSSc). In control fibroblasts, VP selectively reduced expression of fibrogenic genes and also blocked the ability of TGFbeta to induce actin stress fibers in dermal fibroblasts. VP also reduced the persistent profibrotic phenotype of dermal fibroblasts cultured from fibrotic lesions of patients with dcSSc. Our results are consistent with the notion that, in the future, YAP1 inhibitors may represent a novel, valuable method of treating fibrosis as seen in dcSSc.