For cardiac cell therapy to be effective, newly formed immature cardiomyocytes need to structurally and functionally integrate with the existing myocardium. Unfortunately, testing the electro-chemo-mechanical coupling of mature and immature cardiomyocytes in vivo is difficult. Here we engineered two cell μtissues containing combinations of mouse neonate, ES-derived, and iPS-derived cardiac myocytes on flexible substrates and utilized ratiometric calcium detection and traction force microscopy to measure excitation-contraction coupling in individual cells and in the pairs. We found that SC-derived cardiac myocytes can structurally couple with neonate cardiomyocytes to functionally support synchronous contraction, yet diastolic calcium levels were reduced in SC-derived cardiomyocytes. Consistently, neonate cardiomyocytes exerted peak systolic forces that were ~1.5-fold higher than that generated by SC-derived myocytes, yielding an imbalance in tension within the pair that was dissipated by focal adhesion-like structures at the cell-cell boundary. Finally we developed a finite element model of two-cell tissue contraction to demonstrate that an imbalance in isometric tension is sufficient to limit force transmission across cell-cell boundaries. Taken together, these results suggest that reduced force transmission between poorly coupled immature and native cardiomyocytes may explain the incomplete repair of ejection fraction observed in several clinical studies of cardiac cell therapy.
Prospects for pluripotent stem cell-derived cardiomyocytes in cardiac cell therapy and as disease models