Mechanosensor YAP cooperates with TGF-β1 signaling to promote myofibroblast activation and matrix stiffening in a 3D model of human cardiac fibrosis

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Cardiac fibrosis is characterized by a maladaptive remodeling of the myocardium, which is controlled by various inflammatory pathways and cytokines. This remodeling is accompanied by a significant stiffening of the matrix, which may contribute to further activate collagen synthesis and scar formation. Evidence suggests that TGF-β1 signaling, the main pro-fibrotic pathway in cardiac fibrosis, might cooperates with the Hippo transcriptional pathway by activating YAP. To directly test the cooperation of mechanical cues and paracrine signaling in cardiac fibrosis, we developed a 3D model of cardiac extracellular matrix remodeling by generating tissue blocks with Gelatin Methacrylate, a bioink with tunable stiffness, and human cardiosphere-derived stromal cells. Using this strategy, we assessed the cooperation of TGFβ1 and YAP transcriptional factor to matrix compaction. Using mechanical compression tests, Masson’s trichrome staining, immunofluorescence, and RT-qPCR, we demonstrate that pharmacological inhibition of YAP complex reverts almost completely the pro-compaction phenotype and the matrix-remodeling activity of cells treated with TGF-β1. Our data show a direct connection between the classical pro-fibrotic signaling driven by TGF-β1 and the mechanically activated pathways under the control of YAP in cardiac remodeling. Treatment with the elective drug targeting YAP is sufficient to override this cooperation with potential benefits for anti-fibrotic therapeutic applications