Generating ring-shaped engineered heart tissues from ventricular and atrial human pluripotent stem cell-derived cardiomyocytes

Idit Goldfracht, Stephanie Protze, Assad Shiti, Noga Setter, Amit Gruber, Naim Shaheen, Yulia Nartiss, Gordon Keller and Lior Gepstein ()
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Idit Goldfracht: Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, the Rappaport Faculty of Medicine and Research Institute, Technion‒Israel Institute of Technology, Haifa, Israel, POB 9649
Stephanie Protze: University Health Network
Assad Shiti: Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, the Rappaport Faculty of Medicine and Research Institute, Technion‒Israel Institute of Technology, Haifa, Israel, POB 9649
Noga Setter: Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, the Rappaport Faculty of Medicine and Research Institute, Technion‒Israel Institute of Technology, Haifa, Israel, POB 9649
Amit Gruber: Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, the Rappaport Faculty of Medicine and Research Institute, Technion‒Israel Institute of Technology, Haifa, Israel, POB 9649
Naim Shaheen: Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, the Rappaport Faculty of Medicine and Research Institute, Technion‒Israel Institute of Technology, Haifa, Israel, POB 9649
Yulia Nartiss: University Health Network
Gordon Keller: University Health Network
Lior Gepstein: Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, the Rappaport Faculty of Medicine and Research Institute, Technion‒Israel Institute of Technology, Haifa, Israel, POB 9649

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract The functions of the heart are achieved through coordination of different cardiac cell subtypes (e.g., ventricular, atrial, conduction-tissue cardiomyocytes). Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer unique opportunities for cardiac research. Traditional studies using these cells focused on single-cells and utilized mixed cell populations. Our goal was to develop clinically-relevant engineered heart tissues (EHTs) comprised of chamber-specific hPSC-CMs. Here we show that such EHTs can be generated by directing hPSCs to differentiate into ventricular or atrial cardiomyocytes, and then embedding these cardiomyocytes in a collagen-hydrogel to create chamber-specific, ring-shaped, EHTs. The chamber-specific EHTs display distinct atrial versus ventricular phenotypes as revealed by immunostaining, gene-expression, optical assessment of action-potentials and conduction velocity, pharmacology, and mechanical force measurements. We also establish an atrial EHT-based arrhythmia model and confirm its usefulness by applying relevant pharmacological interventions. Thus, our chamber-specific EHT models can be used for cardiac disease modeling, pathophysiological studies and drug testing.

Date: 2020
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DOI: 10.1038/s41467-019-13868-x

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