Verteporfin inhibits the persistent fibrotic phenotype of lesional scleroderma dermal fibroblasts

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.

Age-Related Downregulation of CCN2 Is Regulated by Cell Size in a YAP/TAZ-Dependent Manner in Human Dermal Fibroblasts: Impact on Dermal Aging

“…YAP nuclear localization/activation is exquisitely sensitive to cell size and mechanical tension (Dupont et al, 2011), and constitutive nuclear localization of YAP is a feature of lesional systemic sclerosis dermal fibroblasts (Toyama et al, 2018, Zanconato et al, 2016. In supporting this notion, a recent work demonstrates that blocking YAP activity using a selective YAP inhibitor verteporfin selectively blocks profibrotic J o u r n a l P r e -p r o o f gene expression in both normal fibroblasts and fibroblasts from fibrotic lesions of patients with diffuse cutaneous systemic sclerosis (Shi-Wen et al, 2021). YAP inhibitor verteporfin not only selectively reduced expression of fibrogenic genes but also blocked the ability of TGF-β to induce actin stress fibers in dermal fibroblasts.…”

Mechanotransduction in Skin Inflammation

“…IL-17A, one of the main drivers of psoriatic inflammation, is able to activate YAP pathway in keratinocytes in vitro [239]. YAP/TAZ upregulation has been associated with the pathogenesis of systemic sclerosis [240,241]. Rho-dependent YAP activation by diverse ligands of the G-protein-coupled receptors (GPCR) might act in synergy with TGF-β1 to reinforce the pro-fibrotic program in human dermal fibroblasts, whereas the inhibition of YAP/TAZ limits the TGF-β signaling, myofibroblast differentiation, and skin fibrosis in mouse models [31,241].…”

“…YAP/TAZ upregulation has been associated with the pathogenesis of systemic sclerosis [240,241]. Rho-dependent YAP activation by diverse ligands of the G-protein-coupled receptors (GPCR) might act in synergy with TGF-β1 to reinforce the pro-fibrotic program in human dermal fibroblasts, whereas the inhibition of YAP/TAZ limits the TGF-β signaling, myofibroblast differentiation, and skin fibrosis in mouse models [31,241]. Moreover, the crosstalk between YAP/TAZ, NFκB, and β-catenin signaling may have complex positive and negative effects on inflammatory responses [242,243].…”

Canadian Contributions in Fibroblast Biology

“…CCN1 secreted from fibroblasts plays a major contributory role in skin fibrosis via the regulation of collagen synthesis, while CCN2 regulates myofibroblast activation, making both molecules intriguing anti-fibrotic targets [ 82 ]. His recent work has focused on repurposing verteporfin, a drug used in the treatment of macular degeneration, to inhibit the transcription co-activator YAP, which itself plays a major role in regulating expression levels of CCN1 and CCN2, as a novel approach to treating fibrosis [ 83 ]. Recent work from the Dixon laboratory has examined YAP/TAZ signaling in the Hippo pathway in cardiac fibroblast activation, and demonstrates that SKI induces proteasomal degradation of TAZ to inhibit the myofibroblast phenotype [ 84 ].…”