Naturally aligned cell delivery platform to augment post-infarction neovasculature and ventricular remodeling

We demonstrated that joint delivery of human-derived endothelial progenitor cell (EPC) and smooth muscle cell (SMC) sheets mimics the native architecture of structurally mature blood vessels and contributes to limiting ventricular remodeling using a confluent SMC-EPC bi-level cell sheet engineered by cell-sheet technology and transplanted into an athymic rodent model of myocardial infarction. Enhanced vasculogenic potential was observed in vitro when EPCs were stimulated with SMC-conditioned culture medium, augmenting angiogenesis in vivo. Increased structurally mature vessel density, myocardial upregulation of biological adhesion, and vasculature developmental genes in the ischemic border zone myocardium showed interaction between cells and the extracellular matrix. Cell fate tracking experiments featuring xenogeneic transplantation showed transplanted EPCs and SMCs to have elements of the newly formed vasculature. Specialized magnetic resonance imaging of the cell-sheet-transplanted rodents suggested prolonged cell retention. The robust angiogenic effect of the transplanted cell sheets induced reverse ventricular remodeling of the ischemic heart. Bioinformatic analyses indicated that these cell sheets promote transcriptome-wide changes in the left ventricular response to acute ischemia, promote productive remodeling, and prevent pathological ventricular dilation. Thus, the human-derived, spatially arranged SMC-EPC bi-level cell sheet is a promising therapy for increasing myocardial viability and limiting adverse ventricular remodeling after myocardial infarction.