Key differences in hypertrophic signalling between hESC- and hIPSC-derived cardiomyocytes

Abstract

The potential of stem cell-based disease modelling is enhanced by the realisation that cardiomyocytes from human embryonic stem cells (hESC-CM) and induced pluripotent stem cells (hiPSC-CM) can be obtained with disease-specificity. Hypertrophy is a high priority target because of its central role in the transition to heart failure. Strikingly, here we found that hiPSC-CM are relatively unresponsive to major hypertrophic signals compared to hESC-CM. We show that the normal alpha-adrenergic receptor 1A subtype (ADRA1A) is not expressed robustly in either cell type. ADRA1A is reversibly silenced during differentiation, accompanied by up-regulation of ADRA1B, resulting in a distinct gene profile from that in adult human cardiomyocytes. Loss of ADRA1A is more pronounced in hiPSC-CM, due to greater epigenetic silencing and more marked up-regulation of HIF-1α, but ultimately both cell types differ from adult in their reliance on active ADRA1B rather than ADRA1A. ADRA1B up-regulation is sufficient in hESC-CM for hypertrophic changes such as cell size, cell volume and ANF. However, in hiPSC-CM, additional decreased G-protein signalling and tonically inhibitory pathway networks suppress the effect of alpha-adrenoceptor stimulation on growth. Superficial similarities between hESC-CM, hiPSC-CM and adult cardiomyocytes may mask complex differences in signalling. These data raise serious questions regarding the hiPSC-CM as a valid model system for certain aspects of cardiac disease.