Engineered Macroscale Cardiac Constructs Elicit Human Myocardial Tissue-like Functionality

Summary In vitro surrogate models of human cardiac tissue hold great promise in disease modeling, cardiotoxicity testing, and future applications in regenerative medicine. However, the generation of engineered human cardiac constructs with tissue-like functionality is currently thwarted by difficulties in achieving efficient maturation at the cellular and/or tissular level. Here, we report on the design and implementation of a platform for the production of engineered cardiac macrotissues from human pluripotent stem cells (PSCs), which we term “CardioSlice.” PSC-derived cardiomyocytes, together with human fibroblasts, are seeded into large 3D porous scaffolds and cultured using a parallelized perfusion bioreactor with custom-made culture chambers. Continuous electrical stimulation for 2 weeks promotes cardiomyocyte alignment and synchronization, and the emergence of cardiac tissue-like properties. These include electrocardiogram-like signals that can be readily measured on the surface of CardioSlice constructs, and a response to proarrhythmic drugs that is predictive of their effect in human patients.
Highlights • Human iPSC-derived cardiomyocytes are cultured in ∼1-mm-thick constructs • Continuous electrical stimulation greatly enhances maturation at the tissue level • Electrostimulated constructs (CardioSlice) generate ECG-like bioelectrical signals • CardioSlice response to proarrhythmic drugs is predictive of effect in patients
In this article, Raya and colleagues design and implement a cardiac tissue-engineering platform for the production of macrotissues from human pluripotent stem cells. These human cardiac macrotissues can be electrically stimulated, and their electric activity recorded from the surface of the constructs. After 2 weeks of electrical stimulation, distinct cardiac tissue-like properties appear such as electrocardiogram-like signals and patient-like response to cardiotoxic drugs.