Time-dependent evolution of functional vs. remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for uncovering disease mechanisms and assessing drugs for efficacy/toxicity. However, the accuracy with which hiPSC-CMs recapitulate the contractile and remodeling signaling of adult cardiomyocytes is not fully known. We used beta-adrenergic receptor (beta-AR) signaling as a prototype to determine the evolution of signaling component expression and function during hiPSC-CM maturation. In early hiPSC-CMs (less than or equal to d 30), beta 2-ARs are a primary source of cAMP/PKA signaling. With longer culture, beta 1-AR signaling increases: from 0% of cAMP generation at d 30 to 56.8 +/- 6.6% by d 60. PKA signaling shows a similar increase: 15.7+/-5.2%(d 30), 49.8+/-0.5%(d 60), and 71.0+/-6.1% (d 90). cAMP generation increases 9-fold from d 30 to 60, with enhanced coupling to remodeling pathways (e.g., Akt and Ca2+/calmodulin-dependent protein kinase type II) and development of caveolin-mediated signaling compartmentalization. By contrast, cardiotoxicity induced by chronic beta-AR stimulation, a major component of heart failure, develops much later: 5% cell death at d 30 vs. 55% at d 90. Moreover, beta-AR maturation can be accelerated by biomechanical stimulation. The differential maturation of beta-AR functional vs. remodeling signaling in hiPSC-CMs has important implications for their use in disease modeling and drug testing. We propose that assessment of signaling be added to the indices of phenotypic maturation of hiPSC-CMs.-Jung, G., Fajardo, G., Ribeiro, A. J. S., Kooiker, K. B., Coronado, M., Zhao, M., Hu, D.-Q., Reddy, S., Kodo, K., Sriram, K., Insel, P. A., Wu, J. C., Pruitt, B. L., Bernstein, D. Time-dependent evolution of functional vs. remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation. FASEB J. 30, 1464-1479 (2016). www.fasebj.org