Strategies to Enhance Engineered Heart Tissue Based Myocardial Repair

PROJECT SUMMARY Ischemic heart disease, such as unstable coronary angina or myocardial infarction, often leads to systolic heart failure due to the loss of contractile cardiomyocytes. Engineered heart tissue mediated transplantation of stem cell derived cardiomyocytes holds the promise to regenerate the myocardium and improve cardiac function post myocardial infarction in preclinical animal models. Despite these encouraging results, several critical barriers limit the clinical application of engineered heart tissue-based therapy. For example, the poor perfusion in the infarct area compromises the survival of transplanted cardiomyocytes. In addition, the procedure of transplantation of engineered heart tissue typically requires open chest surgery which is a significant challenge to the patients with severe heart failure. Data from our previous studies showed that promoting cell cycle and proliferation in human induced pluripotent stem cells (hiPSC-CMs) constitutes a viable approach to enhance engraftment and restore function in ischemic heart disease. We also generated a new type of nanoparticles that enable myocardial protection via increased vasculogenesis in the ischemic heart. Furthermore, we established an injectable and shape-recoverable tissue with GelMA-coated nanofiber scaffolds. In this project, we aimed to develop novel approaches to enhance the engraftment of implanted hiPSC-CMs via integrating nanomaterials, cell- and tissue-engineering technologies. Specifically, we will 1) develop a novel engineered heart tissue which leverages the capacity of nanomaterials to release pro-vasculogenic molecules and promote revascularization in these engineered heart tissues and in the infarct heart; 2) take the advantage of our recently established protocol to induce the proliferation of survival cardiomyocytes inside the engineered heart tissues; and 3) study if delivery of these novel engineered heart tissues to animals with acute or chronic myocardial infarction leads to robust myocardial regeneration and repair.