PDF(Pubmed)
Abstract：
Experimental evidence, both in vitro and in vivo, has indicated cardioprotective effects of extracellular vesicles (EVs) derived from various cell types, including induced pluripotent stem cell-derived cardiomyocytes. The biological effects of EV secretion, particularly in the context of ischemia and cardiac electrophysiology, remain to be fully explored. Therefore, the goal of this study was to unveil the effects of exosome (EXO)-mediated cell-cell signaling during hypoxia by employing a simulated preconditioning approach on human-induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs). Electrophysiological activity of hIPSC-CMs was measured using a multielectrode array (MEA) system. A total of 16 h of hypoxic stress drastically increased the beat period. Moreover, hIPSC-CMs preconditioned with EXOs displayed significantly longer beat periods compared with non-treated cells after 16 h of hypoxia (+15.7%, p < 0.05). Furthermore, preconditioning with hypoxic EXOs resulted in faster excitation-contraction (EC) coupling compared with non-treated hIPSC-CMs after 16 h of hypoxia (-25.3%, p < 0.05). Additionally, microRNA (miR) sequencing and gene target prediction analysis of the non-treated and pre-conditioned hIPSC-CMs identified 10 differentially regulated miRs and 44 gene targets. These results shed light on the intricate involvement of miRs, emphasizing gene targets associated with cell survival, contraction, apoptosis, reactive oxygen species (ROS) regulation, and ion channel modulation. Overall, this study demonstrates that EXOs secreted by hIPSC-CM during hypoxia beneficially alter electrophysiological properties in recipient cells exposed to hypoxic stress, which could play a crucial role in the development of targeted interventions to improve outcomes in ischemic heart conditions.
摘要：
实验证据,在体外和体内，表明了来自各种细胞类型的细胞外囊泡（EV）的心脏保护作用，包括诱导多能干细胞衍生的心肌细胞。EV分泌的生物学效应，特别是在缺血和心脏电生理学的背景下，还有待充分探索。因此,本研究的目的是通过采用模拟预处理方法,揭示缺氧期间外泌体(EXO)介导的细胞-细胞信号传导对人诱导的多能干细胞源性心肌细胞(hIPSC-CMs)的影响.使用多电极阵列（MEA）系统测量hIPSC-CM的电生理活性。总共16小时的低氧应激急剧增加了搏动周期。此外，缺氧16小时后，与未处理的细胞相比，用EXOs预处理的hIPSC-CM显示明显更长的搏动期（+15.7%，p<0.05)。此外，与未处理的hIPSC-CM相比，用缺氧EXO预处理在缺氧16小时后导致更快的兴奋-收缩（EC）耦合（-25.3％，p<0.05)。此外,未处理和预处理的hIPSC-CM的microRNA(miR)测序和基因靶预测分析鉴定了10个差异调节的miR和44个基因靶。这些结果揭示了miR的复杂参与，强调与细胞存活相关的基因靶标，收缩，凋亡，活性氧（ROS）调节，和离子通道调制。总的来说,这项研究表明，在缺氧期间由hIPSC-CM分泌的EXOs有益地改变暴露于低氧应激的受体细胞的电生理特性，这可能在制定针对性干预措施以改善缺血性心脏病的预后方面发挥关键作用。
