Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block.
Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block.
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DOI：
10.1126/scitranslmed.3008681
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发表时间：
2014-07-16
影响因子：
17.1
通讯作者：
Cingolani E
中科院分区：
文献类型：
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作者：
Hu YF;Dawkins JF;Cho HC;Marbán E;Cingolani E
体细胞重编程通过胚胎转录因子T-box 18 （TBX18）的重表达将心肌细胞转化为起搏器细胞。我们假设这可能是一种可行的治疗途径，用于患有器械相关并发症的起搏器依赖患者，因此，在完全心脏传导阻滞的大型动物模型中，我们测试了腺病毒TBX18基因转移是否可以在体内产生生物起搏器活性。生物起搏器的活性，起源于心肌内注射部位，在tbx18转导的动物中，从第2天开始就很明显，并持续了整个研究期间（14天），使用了最少的备用电子起搏器。与报告基因转导的对照组相比，tbx18转导的动物表现出增强的自主神经反应和生理上优越的体力活动变时性支持。诱导的窦房结细胞可以通过tbx18转导动物注射部位的独特形态来识别，但在对照组中没有。没有出现局部或系统性的安全问题。因此，微创TBX18基因转移在完全性心脏传导阻滞中产生了生理相关的起搏器活动，为临床相关疾病模型中的治疗性体细胞重编程提供了证据。
Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create biological pacemaker activity in vivo in a large-animal model of complete heart block. Biological pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model.