Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts

Abstract

Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure 1 by providing human cardiomyocytes to support heart regeneration 2. Studies of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in small animal models have shown favorable effects of this treatment 3–7. It remains unknown, however, whether clinical scale hESC-CMs transplantation is feasible, safe or can provide large-scale myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (>1 billion cells/batch) and cryopreserved with good viability. Using a non-human primate (NHP) model of myocardial ischemia-reperfusion, we show that that cryopreservation and intra-myocardial delivery of 1 billion hESC-CMs generates significant remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a three-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small animal models 7, non-fatal ventricular arrhythmias were observed in hESC-CM engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome.

We heart cultured hearts. A comparative review of methodologies for targeted differentiation and maintenance of cardiomyocytes derived from pluripotent and multipotent stem cells

“…It is also notable that while cardiomyocytes derived by targeted differentiation from embryonic stem cells were shown to alleviate arrhythmia when transplanted in injured myocardium; other authors have demonstrated that cardiomyocytes derived from hESC may possess inherent pro-arrhythmic potential [76,77]. Non-fatal ventricular arrhythmias were observed in macaques that have received intracardially cardiomyocytes derived from differentiation of hESC [59]. The authors of the cited study specifically noted that this was not observed in previous experiments with small-animal models.…”

“…The results were encouraging, as pigs with transplanted cells exhibited improved cardiac neo-angiogenesis. Transplantations of cardiomyocytes derived in vitro from mESC into hearts of non-human primate (macaque) models of myocardial infarction were reported to result in apparent remuscularisation of the infarcted region [59]. The transplanted cells were perfused by the vascular system of the recipient and exhibited Ca 2+ transients synchronised to the recipient's ECG.…”

New Strategies for Myocardial Infarction Treatment

“…It has been extensively investigated for the repair of the infarcted heart. Studies in animal models have shown promising effects of embryonic stem cell-derived cardiomyocytes (ESC-CMs) treatment [15,16] . Transplantation of human ESC-CMs in a non-human primate (NHP) model of myocardial ischemia-reperfusion showed evident remasculinization, but potential arrhythmic complications remain unsolved [15] .…”

“…Studies in animal models have shown promising effects of embryonic stem cell-derived cardiomyocytes (ESC-CMs) treatment [15,16] . Transplantation of human ESC-CMs in a non-human primate (NHP) model of myocardial ischemia-reperfusion showed evident remasculinization, but potential arrhythmic complications remain unsolved [15] . Currently, there are four major reasons that hinder the clinical application of ESC: Firstly, the transplanted embryonic stem cells may differentiate into unwanted cell types in the human body.…”

Hypoxia-preconditioned allogeneic mesenchymal stem cells can be used for myocardial repair in non-human primates

“…Infarct size and left ventricular function 90 days after MI were measured using magnetic resonance imaging and positron emission tomography, and monkeys treated with hypoxic MSCs, but not normoxic MSCs, had significant improvements in infarct size and function compared with monkeys treated with the control vehicle. Hypoxic MSC transplantation was also associated with increases in endogenous cardiomyocyte survival and proliferation, glucose uptake, vascular density, and engraftment of the transplanted cells but did not cause long-term arrhythmogenic complications, which were observed in non-human primate hearts treated with human embryonic-stem-cell-derived cardiomyocytes (14). Because Hu et al did not observe neocardiomyogenesis and the engraftment rates for normoxic and hypoxic MSCs were low, the benefit of hypoxic MSC transplantation was likely due to the upregulation of transcription factors or the secretion of paracrine factors that stimulated endogenous cytoprotective or regenerative mechanisms.…”