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.人间充质干细胞（human mesenchymal stem cell, hMSC）移植在心肌梗死治疗的临床前与临床试验中已展现出应用前景，但由于对hMSC与人心肌细胞（human cardiomyocyte, hCM）之间相互作用的认知不足，其临床广泛应用仍受到限制。为更深入理解hMSC与hCM之间直接异细胞连接所产生的电生理效应，本研究构建了三种原创数学模型，用以表征经实验验证的三类具有不同功能离子通道电流的hMSC亚群。通过将这些hMSC模型与已发表的ten Tusscher心肌中层hCM模型进行耦合与融合，本研究预测了健康成年心肌环境中此类直接电相互作用的致心律失常风险。当hCM与两种表达功能性延迟整流型人ether-à-go-go钾通道1（human ether à-go-go K+ channel 1, hEAG1）的hMSC模型耦合时，可观察到动作电位波形出现显著变化，例如动作电位时程（action potential duration, APD）缩短与平台高度降低；当形成融合的hMSC-hCM杂交细胞时，上述效应会进一步加剧。第三类hMSC亚群（C型）不表达hEAG1活性，其耦合与融合过程仅引发轻微的单细胞动作电位改变，对应组织层面的平均动作电位波长更长。在模拟的二维心肌组织单层中，当hMSC植入比例为5%（低水平）时，C型hMSC的折返易感性较表达hEAG1的功能性hMSC低约8倍。与表达hEAG1的hMSC相比，C型hMSC可使动作电位时程离散度降低20%，这支持了"低水平hMSC-hCM耦合时，不表达hEAG1活性的hMSC亚群可降低致心律失常潜力"这一结论。然而，当hMSC植入比例为中等水平（15%）与高水平（25%）时，无论hMSC亚群类型如何，易损窗口均会增大。综上，本研究构建了全新的hMSC电生理模型，预测了hMSC直接耦合至健康hCM时可能产生的致心律失常效应，并提出：分离不表达hEAG1活性的hMSC亚群，在低水平hMSC-hCM耦合的细胞移植心脏治疗中可提升治疗安全性。