A better understanding of structural and functional interactions between cardiac and non-cardiac cells is essential to better address the sequelae of cardiac disease and improve the potential cellular implantation therapies. First, an in vitro model was established to investigate the probability that electromechanical junctions form between cardiac and non-cardiac cells. Soft lithography techniques were used to create abutting-trapezoid shaped protein islands that supported the formation of isolated cell pairs with a defined cell-cell contact interface. After assessing connexin 43 and N-cadherin expression, higher chances for functional coupling with host cardiomyocytes exist for mesenchymal stem cells (MSC), followed by skeletal myoblasts (SKM), and finally cardiac fibroblasts (CF).

Second, we studied the effect resulting from factors secreted by (1) donor cells (SKMs or MSCs) and (2) cardiac fibroblasts on the electrophysiological properties (EP) of 2-D cardiac networks in vitro. Specifically, we conditioned a defined serum-free media (control media) for 24 hours in the presence of non-cardiac cells and assessed electrophysiological properties. Our results indicate that (1) that paracrine factors secreted by cardiac fibroblasts could contribute to the progression of fibrotic cardiac disease, (2) that there may be a crosstalk mechanism between CFs and cardiomyocytes that prevents this paracrine action to occur in a healthy heart, which could be exploited for possible future cardiac therapies, and finally (3) that protection of cardiomyocytes from the negative paracrine action of CFs in a post-infarcted heart may be another possible mechanism of how donor cells used in cardiomyoplasty improve cardiac function without cellular engraftment.

In summary, this research represents one of the steps towards the ultimate design of safe and effective therapies for the restoration of heart function after myocardial infarction.