Modeling Electrophysiological Coupling and Fusion between Human Mesenchymal Stem Cells and Cardiomyocytes

Human mesenchymal stem cell (hMSC) delivery has demonstrated promise in preclinical and clinical trials for myocardial infarction therapy; however, broad acceptance is hindered by limited understanding of hMSC-human cardiomyocyte (hCM) interactions. To better understand the electrophysiological consequences of direct heterocellular connections between hMSCs and hCMs, three original mathematical models were developed, representing an experimentally verified triad of hMSC families with distinct functional ion channel currents. The arrhythmogenic risk of such direct electrical interactions in the setting of healthy adult myocardium was predicted by coupling and fusing these hMSC models to the published ten Tusscher midcardial hCM model. Substantial variations in action potential waveform—such as decreased action potential duration (APD) and plateau height—were found when hCMs were coupled to the two hMSC models expressing functional delayed rectifier-like human ether à-go-go K+ channel 1 (hEAG1); the effects were exacerbated for fused hMSC-hCM hybrid cells. The third family of hMSCs (Type C), absent of hEAG1 activity, led to smaller single-cell action potential alterations during coupling and fusion, translating to longer tissue-level mean action potential wavelength. In a simulated 2-D monolayer of cardiac tissue, re-entry vulnerability with low (5%) hMSC insertion was approximately eight-fold lower with Type C hMSCs compared to hEAG1-functional hMSCs. A 20% decrease in APD dispersion by Type C hMSCs compared to hEAG1-active hMSCs supports the claim of reduced arrhythmogenic potential of this cell type with low hMSC insertion. However, at moderate (15%) and high (25%) hMSC insertion, the vulnerable window increased independent of hMSC type. In summary, this study provides novel electrophysiological models of hMSCs, predicts possible arrhythmogenic effects of hMSCs when directly coupled to healthy hCMs, and proposes that isolating a subset of hMSCs absent of hEAG1 activity may offer increased safety as a cell delivery cardiotherapy at low levels of hMSC-hCM coupling.Author Summary: Myocardial infarction—better known as a heart attack—strikes on average every 43 seconds in America. An emerging approach to treat myocardial infarction patients involves the delivery of human mesenchymal stem cells (hMSCs) to the damaged heart. While clinical trials of this therapeutic approach have yet to report adverse effects on heart electrical rhythm, such consequences have been implicated in simpler experimental systems and thus remain a concern. In this study, we utilized mathematical modeling to simulate electrical interactions arising from direct coupling between hMSCs and human heart cells to develop insight into the possible adverse effects of this therapeutic approach on human heart electrical activity, and to assess a novel strategy for reducing some potential risks of this therapy. We developed the first mathematical models of electrical activity of three families of hMSCs based on published experimental data, and integrated these with previously established mathematical models of human heart cell electrical activity. Our computer simulations demonstrated that one particular family of hMSCs minimized the disturbances in cardiac electrical activity both at the single-cell and tissue levels, suggesting that isolating this specific sub-population of hMSCs for myocardial delivery could potentially increase the safety of future hMSC-based heart therapies.