Proarrhythmic potential of mesenchymal stem cell transplantation revealed in an in vitro coculture model

Background - Mesenchymal stem cells (MSCs) are bone marrow stromal cells that are in phase 1 clinical studies of cellular cardiomyoplasty. However, the electrophysiological effects of MSC transplantation have not been studied. Although improvement of ventricular function would represent a positive outcome of MSC transplantation, focal application of stem cells has the potential downside of creating inhomogeneities that may predispose the heart to reentrant arrhythmias. In the present study we use an MSC and neonatal rat ventricular myocyte (NRVM) coculture system to investigate potential proarrhythmic consequences of MSC transplantation into the heart. Methods and Results - Human MSCs were cocultured with NRVMs in ratios of 1: 99, 1: 9, and 1: 4 and optically mapped. We found that conduction velocity was decreased in cocultures compared with controls, but action potential duration (APD(80)) was not affected. Reentrant arrhythmias were induced in 86% of cocultures containing 10% and 20% MSCs (n = 36) but not in controls ( n = 7) or cocultures containing only 1% MSCs ( n = 4). Immunostaining, Western blot, and dye transfer revealed the presence of functional gap junctions involving MSCs. Conclusions - Our results suggest that mixtures of MSCs and NRVMs can produce an arrhythmogenic substrate. The mechanism of reentry is probably increased tissue heterogeneity resulting from electric coupling of inexcitable MSCs with myocytes.