Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell-Derived Exosomes From Pediatric Patients.
Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell-Derived Exosomes From Pediatric Patients.
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DOI：
10.1161/circresaha.116.309935
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发表时间：
2017-02-17
影响因子：
20.1
通讯作者：
Davis ME
中科院分区：
文献类型：
--
作者：
Agarwal U;George A;Bhutani S;Ghosh-Choudhary S;Maxwell JT;Brown ME;Mehta Y;Platt MO;Liang Y;Sahoo S;Davis ME
研究表明，外切体可以修复心肌梗死(MI)后的心脏组织，并概括了细胞治疗的好处。在大鼠缺血再灌注损伤模型中，我们评估了供者年龄和儿童心脏前体细胞(CPC)来源的外切体缺氧的作用。在低氧和常氧条件下，从不同年龄先天性心脏病手术患儿的右心耳分离培养CPC。从培养条件培养液中分离外切体，并将其传递给IR损伤后的无菌大鼠。心肌梗死后第3天的超声心动图显示，与生理盐水处理的对照组相比，新生儿低氧组和正常氧组的功能有统计学上的改善。在心肌梗死后28天，来自新生儿常氧、新生儿低氧、婴儿低氧和儿童低氧的外体与生理盐水处理的对照组相比显著改善了心功能。染色显示，与对照组相比，低氧组肝纤维化减轻，血管生成增加。最后，利用测序数据，生成了一个计算模型，将microRNA水平与特定结果联系起来。来自新生儿的CPC外切酶体能改善心功能，而不依赖于培养氧水平，而来自较大儿童的CPC-Exosome除非受到低氧条件的影响，否则不能修复。心功能的改善与血管生成增加、纤维化减少和肥厚改善有关，从而改善了心功能；然而，常氧条件下新生儿CPC外切体改善功能的机制独立于这些机制。这是这类研究的第一次，表明供体年龄和微环境中的氧含量显著改变了人类CPC来源的外切体的效果。
Studies have demonstrated that exosomes can repair cardiac tissue post myocardial infarction (MI) and recapitulate the benefits of cellular therapy. We evaluated the role of donor age and hypoxia of human pediatric cardiac progenitor cell (CPC)-derived exosomes, in a rat model of ischemia reperfusion (IR) injury. Human CPCs from the right atrial appendages from children of different ages undergoing cardiac surgery for congenital heart defects were isolated and cultured under hypoxic or normoxic conditions. Exosomes were isolated from the culture-conditioned media and delivered to athymic rats following IR injury. Echocardiography at day-3 post-MI suggested statistically improved function in neonatal hypoxic and neonatal normoxic groups compared to saline-treated controls. At 28 days post-MI exosomes derived from neonatal normoxia, neonatal hypoxia, infant hypoxia, and child hypoxia significantly improved cardiac function compared to saline-treated controls. Staining showed decreased fibrosis and improved angiogenesis in hypoxic groups compared to controls. Finally, using sequencing data, a computational model was generated to link microRNA levels to specific outcomes. CPC exosomes derived from neonates improved cardiac function independent of culture oxygen levels, while CPC-exosomes from older children were not reparative unless subjected to hypoxic conditions. Cardiac functional improvements were associated with increased angiogenesis, reduced fibrosis and improved hypertrophy resulting in improved cardiac function; however, mechanisms for normoxic neonatal CPC exosomes improved function independent of those mechanisms. This is the first study of its kind demonstrating that donor age and oxygen content in the microenvironment significantly alter the efficacy of human CPC-derived exosomes.