Analysis of the regenerative potential of the induced pluripotent stem cells in a model of acute myocardial infarction in mice

Abstract

Principal limitation for generating cardiomyocytes from stem cells is that differentiated cells generally present electrophysiological immature and heterogeneous phenotype, which may hamper their in vitro and in vivo application. The purpose of this study was to examine the effect of NRG-1b and DMSO in the in vitro generation of mature working-type cardiomyocytes from induced pluripotent stem (iPS) cells and to determine their contribution to the cardiac tissue regeneration after acute myocardial infarction (AMI). iPS cells were derived from α-MHC-GFP mice fibroblasts and were in vitro differentiated towards cardiomyocytes by DMSO and/or NRG-1b treatment. iPS cardiac specification and maturation was analyzed by Q-RT-PCR, immunofluorescence, electronic microscopy and patch-clamp techniques. The iPS-derived cardiomyocytes (n=15) or culture-medium as control (n=13) were injected into the peri-infarct region of mice hearts following coronary artery ligation. Echocardiography and histology assessments were performed from 1-8 weeks post-transplantation. iPS cells showed early and robust in vitro cardiogenesis with cardiac gene and protein expression in all cases. Electrophysiological studies demonstrated a more mature ventricular-like cardiac phenotype when cells were treated with NRG-1b and DMSO than with DMSO-treatment alone. In vivo studies in the AMI mouse model demonstrated that iPS-derived CMs preserved cardiac function and induced a positive heart tissue remodeling. Moreover, iPS-CMs engrafted and electromechanically couple into the heart tissue. The combination of NRG-1b and DMSO induced iPS cells differentiation towards mature ventricular-like cardiac cells which, when transplanted in a model of AMI, contributed to preserve the cardiac function and tissue viability.