IGF1 and NRG1 Enhance Proliferation, Metabolic Maturity, and the Force-Frequency Response in hESC-Derived Engineered Cardiac Tissues

Insulin-like growth factor 1 (IGF1) and neuregulin-1β (NRG1) play important roles during cardiac development both individually and synergistically. In this study, we analyze how 3D cardiac tissue engineered from human embryonic stem cell- (hESC-) derived cardiomyocytes and 2D-plated hESC-cardiomyocytes respond to developmentally relevant growth factors both to stimulate maturity and to characterize the therapeutic potential of IGF1 and NRG1. When administered to engineered cardiac tissues, a significant decrease in active force production of ~65% was measured in all treatment groups, likely due to changes in cellular physiology. Developmentally related processes were identified in engineered tissues as IGF1 increased hESC-cardiomyocyte proliferation 3-fold over untreated controls and NRG1 stimulated oxidative phosphorylation and promoted a positive force-frequency relationship in tissues up to 3 Hz. hESC-cardiomyocyte area increased significantly with NRG1 and IGF1