Development of Novel Human Engineered Heart Tissue Models Using Human iPSCs-Derived Cardiomyocytes and Cardiac-Specific Extracellular Matrix

Idit Goldfracht ¹ Rami Shinnawi ¹ Yael Efraim ² Irit Huber ¹ Gil Arbel ¹ Amira Gepstein ¹ Wolfram-Hubertus Zimmermann ³ Marcel Machluf ² Lior Gepstein ¹

¹Rappaport Faculty of Medicine and Research Institute and the, Technion-Israel Institute of Technology
²Faculty of Food and Biotechnology Engineering, Technion-Israel Institute of Technology
³Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf

Cardiac tissue engineering using human Induced pluripotent stem cells derived cardiomyocytes (hiPSCs-CMs) offers unique opportunities for cardiac disease modeling and drug testing. We aimed to combine the hiPSCs-CMs with cardiac-specific extracellular matrix (ECM), and genetically-encoded calcium and voltage reporters to establish clinically-relevant engineered human heart tissue models (EHTs).
The hiPSCs-CMs were combined with an ECM gel derived from decellularized pig hearts for the creation of the EHTs. Immunostainings and TEM analysis revealed the presence of cardiomyocytes in a more mature stage of development within the ECM-EHT. Changes in action-potential and calcium-handling properties were monitored by the use of the genetically-encoded fluorescent indicators ArcLight-A242 and GCaMP5, respectively. In EHTs composed of hiPSC-CMs derived from a long QT syndrome patient, the phenotype of the disease was observed. Finally, the contractile properties of the tissue was measured by a force transducer. In conclusion, by combining hiPSCs-CMs, cardiac-specific ECM, and genetically-encoded indicators we were able to establish a clinically-relevant engineered cardiac-tissue model.