Engineering hPSC-Derived Cardiac Organoids for Heart Regeneration

Cardiovascular disease (CVD) is the leading cause of death worldwide and bears an immense economic burden. CVD can lead to myocardial infarction (MI), also known as “heart attack”, which results in extensive cell death. Adult heart tissue has limited regenerative capacity, and upon injury, once-healthy heart muscle is replaced by fibrotic scar tissue, resulting in diminished heart function. There are currently no treatments to restore lost cardiomyocytes, and the current standard of treatment involves CVD symptom management. Advanced heart failure can only be completely treated with heart transplantation, which faces several challenges including shortage of viable donors and the need for lifelong immunosuppression. Therefore, significant efforts have been devoted to developing alternative approaches to restore heart function, including cell-based therapies. Human pluripotent stem cells (hPSCs) have emerged as a promising cell source for cardiac regeneration due to their scalable production and ability to differentiate into functional cardiac tissue. Transplantation of both dissociated hPSC-derived cardiomyocytes (hPSC-CMs) and hPSC-CMs in tissue engineered constructs have demonstrated strong potential for restoring lost cardiac function in animal models. However, current strategies are limited by low cell survival and engraftment. Furthermore, transplantations of allogenic cardiac cells require careful donor matching and the use of immunosuppressant treatments that put the patient at risk for adverse side effects. One approach to improve engraftment of hPSC-CMs involves prevascularization of tissue engineered structures. To this end, we have developed prevascularized isogenic human cardiac organoids composed of hPSC-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells. To further improve the therapeutic potential of cardiac organoids, we investigated the incorporation of hPSC-derived pericytes to enhance vascular development. We then tested the capacity for isogenic cardiac organoids to promote functional recovery in injured rat hearts. Furthermore, in working towards a more clinically relevant human cardiac organoid, we explored the development of hypoimmunogenic cardiac organoids to evade the host immune response and mitigate concerns of allograft rejection. Finally, we investigated whether hypoimmunogenic cardiac organoids could effectively facilitate functional recovery in our rat injury model. Taken together, this work demonstrates the development of isogenic hPSC-derived cardiac organoids with enhanced therapeutic and translational potential.