Electrically Conductive Stem Cell Derived MicroEngineered Heart Tissue for Regeneration of Injured Myocardium

PROJECT SUMMARY Ischemic heart disease is a leading cause of morbidity and mortality worldwide. The lost cardiomyocytes are replaced with fibrous scar tissue, which leads to maladaptive remodeling, contractile dysfunction, and progresses to congestive heart failure. Stem cell transplantation offers a great potential to repair and possibly regenerate damaged myocardium, thus multiple adult stem/progenitors have been explored. However, the critical barriers in stem cell therapy for cardiac regeneration are the lack of long-term survival, insufficient maturation, and unsuccessful coupling and alignment of grafted cardiomyocytes to the host tissue. This project aims to address these critical limitations through integration of genetically engineered stem cells and electrically conductive nanoengineered hydrogel biomaterials. Specifically, we will develop human engineered heart tissues (EHTs) and explore a new therapeutic approach which leverages the capacity of gold nanorods (GNRs) and hydrogel micro-topographies to induce electrical conductivity, cell maturation and alignment within the EHTs. In addition, we will take the advantage of our recently established techniques to induce proliferation and survival cardiomyocytes within the EHTs. Furthermore, we will investigate whether co-culture of isogenic human induced pluripotent stem cells (hiPSCs)-derived cardiomyocytes (hiPSCs-CMs), endothelial cells (hiPSCs-ECs), smooth muscle cells (hiPSCs-SMCs), and cardiac fibroblasts (hiPSCs-CFs) within the engineered heart tissue promote angiogenesis, engraftment and tissue contractility. Moreover, the efficacy and safety of these novel EHTs, developed in this project, will be evaluated in the preclinical acute rat and chronic pig models of ischemic heart disease, which could potentially aid in clinical trials in treating MI patients.