Human Mesenchymal Stem Cell Paracrine Signaling Counteracts Heterocellular Coupling Effects on Cardiac Contractility and Arrhythomgenicity

Abstract

Myocardial delivery of human mesenchymal stem cells (hMSCs) is an emerging therapy for treating the failing heart. Demonstrated benefits include reduced fibrosis and enhanced contractile function, with predominant mechanisms thought to involve paracrine signaling (PS) and heterocellular coupling (HC) between hMSCs and host myocardium. In this study, we utilized mathematical modeling and three-dimensional human engineered cardiac tissues (hECTs) to test the hypothesis that hMSC-mediated PS enhances cardiac contractility and minimizes arrhythmogenicity, counterbalancing the unfavorable effects of direct HC. Based on published studies, our previous hMSC-cardiomyocyte HC model was modified to incorporate hMSC PS effects on single-cell cardiomyocyte ion channel activity and tissue-level fibrosis. Incorporating an established excitation-contraction model, our simulations of PS-only and combined HC+PS effects of hMSCs on human cardiomyocytes replicated our measurements of contractile function of hECTs under matched experimental hMSC-mediated treatments. For example, model simulations and hECTs both demonstrated that the hMSC-mediated effects were most beneficial under PS-only conditions, where developed force significantly increased by 3.5-fold compared to non-hMSC-supplemented controls during physiologic 1-Hz pacing. Similarly, maximum rates of contraction and relaxation were enhanced by PS-only conditions, and diminished by HC. Counteracting PS and HC effects of hMSCs were also revealed in a vulnerable window (VW) analysis of tissue-level arrhythmogenicity in simulated cardiac tissue with moderate (21%) and high (40%) diffuse fibrosis; hMSC HC+PS conditions had variable effects on VW dependent on the percent of hMSCs delivered, while PS-only conditions consistently decreased the VW, thus minimizing arrhythmogenicity. Together, these findings support our hypothesis, and suggest identifying key hMSC paracrine signaling factors as an alternative hMSC-based cardiac therapy.