Immature human engineered heart tissues engraft in a guinea pig chronic injury model

Engineered heart tissue (EHT) transplantation represents an innovative, regenerative approach for heart failure patients. Late preclinical trials are underway, and a first clinical trial started recently. Preceding studies revealed functional recovery after implantation of in vitro-matured EHT in the subacute stage, whereas transplantation in a chronic injury setting was less efficient. When transplanting matured EHTs, we noticed that cardiomyocytes undergo a dedifferentiation step before eventually forming structured grafts. Therefore, we wanted to evaluate whether immature EHT (EHT^Im) patches can be used for transplantation. Chronic myocardial injury was induced in a guinea pig model. EHT^Im (15×10⁶ cells) were transplanted within hours after casting. Cryo-injury led to large transmural scars amounting to 26% of the left ventricle. Grafts remuscularized 9% of the scar area on average. Echocardiographic analysis showed some evidence of improvement of left-ventricular function after EHT^Im transplantation. In a small translational proof-of-concept study, human scale EHT^Im patches (4.5×10⁸ cells) were epicardially implanted on healthy pig hearts (n=2). In summary, we provide evidence that transplantation of EHT^Im patches, i.e. without precultivation, is feasible, with similar engraftment results to those obtained using matured EHT.