Subscribe to RSS
DOI: 10.1055/s-0034-1367125
Human iPS-cell-derived engineered heart tissue for cardiac repair
Objectives: Engineered heart tissue patches might provide a future option for the therapy of terminal heart failure. Recent advantages in stem cell biology allow the generation of large numbers of human induced pluripotent stem cell derived cardiomyocytes (hiPS-CM). Here we investigated if human iPS-cell derived engineered heart tissue (hEHT) grafts support left ventricular function in infarcted hearts of guinea pigs, a species with a relatively human-like cardiac physiology.
Methods: Human iPS-cells were generated by retroviral reprogramming of dermal fibroblasts. Subsequent cardiac differentiation was performed using an embryoid body-based three-stage differentiation protocol, resulting in ∼50% cardiomyocytes. EHT grafts were created from hiPS-CM (7 million cardiomyocytes per EHT). Left ventricular myocardial cryoinjury was induced in adult female guinea pigs (n = 10). 7 days after injury either hEHT grafts (2 per animal, n = 5) or noncontractile constructs (n = 5) were implanted. Functional parameters were examined by echocardiography at baseline and 7 and 35 days after cryoinfarction. Histological analysis of graft survival was assessed 28 days after transplantation.
Results: Histological and immunohistochemical staining for H&E, Massons Trichrome and dystrophin showed survival of iPS-cell derived cardiomyocytes 28 days after transplantation. Human origin of surviving cardiomyocytes in the scar area was demonstrated by fluorescent-in-situ-hybridization. Echocardiography showed significantly reduced left ventricular ejection fraction (LVEF) and fractional area shortening (FAS) as well as left-ventricular dilatation 7 d after cryoinfarction in all animals. Animals receiving cell-free constructs showed further left ventricular dilatation 35 day after injury, whereas hEHT-implantation attenuated dilatation of the left ventricle. Furthermore echocardiography showed significantly improved left ventricular function (EF and FAS) in the hEHT group compared to animals receiving noncontractile constructs.
Conclusion: This study in a small group of animals provides the first and still early evidence that hiPS-CM EHTs survive after transplantation in infarcted guinea pig hearts and enhance cardiac contractile function in this model of myocardial injury.