Ischemic heart disease continues to have a tremendous impact on public health, shortening lifespan and
impairing the quality of life. The inability of the adult human myocardium to undergo regeneration after a
myocardial infarction has inspired research using cell therapy for myocardial repair. However, clinical trials to
date have shown modest or no benefit, suggesting the need to consider other cell sources and approaches.
In large animal models, derivatives of human pluripotent stem cells have provided promising results, but the
grafts have generally been small, transient, and of limited functional benefit. In addition, there remain
important questions regarding cardiac cells derived from iPSCs, including the optimal delivery strategy,
immunogenicity, maturity, and the ability to couple effectively to the native myocardium without causing
arrhythmias. In this proposal, three integrated projects will address these challenges and advance toward the
long-term goal of utilizing a functional human cardiac tissue patch (hCTP) for repair of ischemic myocardium.
The first project aims to generate novel cell populations, including induced cardiac progenitor cells and
genetically engineered cell lines that will be evaluated for their immunogenicity in a novel humanized mouse
model. These and other cell products, including commercially available sources, will be utilized to generate
large vascularized hCTPs in the second project. The third project will utilize a porcine post-infarction model
to test hCTPs and optimize electrical and vascular integration as assessed by optical mapping technology
and MRI/NMR spectroscopy, respectively. These studies will overcome critical barriers to generating large,
fully functional human cardiac tissues that can be integrated safely into the native myocardium to provide a
powerful new approach for treatment of advanced ischemic heart disease.