Invited: Human Pluripotent Stem Cell Derived Cardiac Tissues: Implications for Cardiovascular Regenerative and Precision Medicine

Lior Gepstein
Rambam Medical Center, Israel
Technion - Israel Institute of Technology, Israel

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. To take the field to the next level we combined the patient-specific hiPSC technology, genome editing; developmental biology-inspired differentiating systems yielding specific cardiomyocyte subtypes; state-of-the-art tissue engineering strategies; optical mapping; and emerging concepts from the fields of optogenetics to generate advance tissue models of human cardiac tissues.

Initially, we established confluent 2-D hiPSC-derived cardiac cell-sheets (hiPSC-CCSs), expressing the genetically-encoded voltage indicator ArcLight. We then demonstrated the ability to use this model to study conduction and arrhythmogenesis, including the impact of electrical remodeling processes, drug testing (evaluating therapeutic mechanisms and pro-arrhythmias), modeling of inherited arrhythmogenic disorders and reentrant circuits.

We then developed 3-D human engineered heart tissue (EHT) models by combing the hPSC-CMs (and even chamber-specific cardiomyocytes) with a collagen or porcine-derive cardiac ECM hydrogel. Immunostaining, gene-expression, optical assessment of action-potentials and conduction velocity, pharmacological, and mechanical force measurements studies were used to characterize the different chamber-specific (atrial vs. ventricular EHTs).

These studies highlighted the unique potentials of hPSC-based cardiac tissue models for cardiac disease modeling, pathophysiological studies, drug testing, and the emerging fields of regenerative and precision medicine.

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