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

Abstract

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.

Keywords

• Induced pluripotent stem cells
• Cardiomyocytes
• Cardiac fibrosis
• Disease model
• Drug screening