Prevascularized, multiple-layered cell sheets of direct cardiac reprogrammed cells for cardiac repair.

We previously demonstrated that the efficiency of direct cardiac reprogramming from fibroblasts could be enhanced via mimicking of the in vivo cardiac microenvironment through coculture with cardiomyocytes and by providing electric cues. In the present study, we developed cell sheets using the direct cardiac reprogrammed cells and a nanothin, nanoporous poly(lactic-co-glycolic acid) membrane. Cell sheets were laid layer-by-layer and prevacularized with endothelial cells between the layers. These prevascularized, multilayered cell sheets were implanted on the epicardium of infarcted rat hearts, which led to an improvement in cardiac function and reduction in adverse cardiac remodeling post-myocardial infarction (MI). Thus, the in vivo mimicking direct cardiac reprogramming and prevascularization technique can enhance the efficiency of cell sheets in clinical applications and provide new opportunities to prevent heart failure following MI.