Although cell-based therapies show potential antiarrhythmic effects that could be mediated by their paracrine action, the mechanisms and the extent of these effects were not deeply explored. We investigated the antiarrhythmic mechanisms of extracellular vesicles secreted by cardiosphere-derived cell extracellular vesicles (CDC-EVs) on the electrophysiological properties and gene expression profile of HL1 cardiomyocytes. HL-1 cultures were primed with CDC-EVs or serum-free medium alone for 48 h, followed by optical mapping and gene expression analysis. In optical mapping recordings, CDC-EVs reduced the activation complexity of the cardiomyocytes by 40%, increased rotor meandering, and reduced rotor curvature, as well as induced an 80% increase in conduction velocity. HL-1 cells primed with CDC-EVs presented higher expression of SCN5A, CACNA1C, and GJA1, coding for proteins involved in I_Na, I_CaL, and Cx43, respectively. Our results suggest that CDC-EVs reduce activation complexity by increasing conduction velocity and modifying rotor dynamics, which could be driven by an increase in expression of SCN5A and CACNA1C genes, respectively. Our results provide new insights into the antiarrhythmic mechanisms of cell therapies, which should be further validated using other models.

中文翻译：

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心球来源的细胞分泌的细胞外囊泡的电生理作用：揭示细胞疗法的抗心律失常特性。

尽管基于细胞的疗法显示出潜在的抗心律失常作用，可能由其旁分泌作用介导，但尚未深入探讨这些作用的机制和程度。我们调查了由心球来源的细胞胞外囊泡（CDC-EVs）分泌的胞外囊泡对HL1心肌细胞的电生理特性和基因表达谱的抗心律失常机制。HL-1培养物仅用CDC-EVs或无血清培养基引发48小时，然后进行光学作图和基因表达分析。在光学测绘记录中，CDC-EV将心肌细胞的激活复杂性降低了40％，转子曲折度增加，转子曲率降低，并且传导速度提高了80％。用CDC-EV引发的HL-1细胞表现出更高的SCN5A，CACNA1C和GJA1分别编码涉及I _Na，I _CaL和Cx43的蛋白质。我们的结果表明，CDC-EVs通过提高传导速度和修改转子动力学来降低激活复杂性，这可能分别由SCN5A和CACNA1C基因表达的增加所驱动。我们的结果为细胞疗法的抗心律失常机制提供了新的见解，应使用其他模型进一步验证。