Cardiac fibrosis models using human induced pluripotent stem cell-derived cardiac tissues allow anti-fibrotic drug screening in vitro

•Multicellular model system using induced pluripotent stem cells to simulate cardiac tissue.•Model cardiac tissue responded appropriately to known fibrotic and anti-fibrotic stimulation.•Multicellular model cardiac tissue allowed evaluation of not only ECM production but also cardiac contraction/relaxation.•Model shows precise response to anti-fibrotic drugs similar to the therapeutic response observed in an in vivo heart failure model. Drug efficacy assessment without using animals is important for development of cardiac fibrosis treatment. In this study, potential anti-fibrotic drugs were screened in a model of diseased myocardium using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and non-CM in in vitro and in vivo heart failure models. Cardiomyogenic differentiation was induced in hiPSC to generate cardiac tissue, including both iPSC-CM and non-CM expressing fibroblast markers. Stimulation with TGF-β significantly increased cardiac fibrotic extracellular matrix (ECM) gene expression, and decreased cardiac contractile/relaxation velocity. Anti-fibrotic HGF significantly decreased fibrotic changes induced by TGF-β. A prostacyclin agonist, ONO-1301 (ONO), camostat mesilate (Cs), and pirfenidone (Pf) significantly decreased fibrotic ECM expression, and improved contraction/relaxation in the model stimulated with TGF-β. Consistent with the in vitro assay, the administration of ONO, Cs, or Pf for 8 weeks in J2N-k hamsters preserved the left ventricular ejection fraction and decreased cardiac fibrosis compared with the controls. The in vitro model simulating fibrotic cardiac tissue showed precise screening of anti-fibrotic drugs which indicated the expected therapeutic response in an in vivo heart failure model, suggesting that the in vitro model presented in this study is a useful tool for the screening of anti-fibrotic drugs.