MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function.
MicroRNA induced cardiac reprogramming in vivo: evidence for mature cardiac myocytes and improved cardiac function.
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MicroRNA在体内诱导心脏重编程：成熟心肌细胞和改善心脏功能的证据。
DOI：
10.1161/circresaha.116.304510
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发表时间：
2015-01-30
影响因子：
20.1
通讯作者：
Dzau VJ
中科院分区：
文献类型：
--
作者：
Jayawardena TM;Finch EA;Zhang L;Zhang H;Hodgkinson CP;Pratt RE;Rosenberg PB;Mirotsou M;Dzau VJ
治疗由心脏损伤损伤的心脏组织的主要目标是开发通过受损心肌的再生和修复来恢复健康心肌的策略。我们最近证明，将特定的micro-RNA组合（miR组合）施用到梗死心肌中导致直接在体内将非心肌细胞重编程为心肌细胞。然而，这种重编程的生物学和功能后果尚不清楚。本研究的目的是确定在体内使用miRNA直接重编程的非心肌细胞是否原位发育为成熟的功能性心肌细胞，以及重编程是否导致心脏功能的改善。我们通过永久性结扎冠状动脉左前降支（LAD）使FSP1-Cre小鼠/tdTomato小鼠遭受心脏损伤，并注射编码miR组合或对照非靶向miRNA的慢病毒。miR组合显著增加了体内重编程事件的数量。损伤后5 - 6周，离体分析了tdTomato-和tdTomato+心肌细胞样细胞的形态学和生理学特性。tdTomato+细胞表达心肌细胞标志物、肌节组织、兴奋-收缩偶联和成熟心室心肌细胞（tdTomato −细胞）的动作电位特征。通过系列超声心动图分析，重新程控与心功能改善相关。缩短分数和心室功能的其他测量值存在时间延迟和进行性改善，表明miR组合促进受损心肌的功能恢复。这项研究的结果进一步验证了miRNA介导的重编程作为一种治疗方法促进心肌损伤后心脏再生的潜在效用。
A major goal for the treatment of heart tissue damaged by cardiac injury is to develop strategies for restoring healthy heart muscle through the regeneration and repair of damaged myocardium. We recently demonstrated that administration of a specific combination of micro-RNAs (miR combo) into the infarcted myocardium leads to direct in vivo reprogramming of non-cardiac myocytes to cardiac myocytes. However, the biologic and functional consequences of such reprogramming are not yet known. The aim of this study was to determine whether non-cardiac myocytes directly reprogrammed using miRNAs in vivo develop into mature functional cardiac myocytes in situ, and whether reprogramming leads to improvement of cardiac function. We subjected FSP1-Cre mice/tdTomato mice to cardiac injury by permanent ligation of the left anterior descending coronary artery (LAD) and injected lentiviruses encoding miR combo or a control nontargeting miRNA. miR combo significantly increased the number of reprogramming events in vivo. Five-to-six weeks following injury, morphological and physiological properties of tdTomato− and tdTomato+ cardiac myocyte-like cells were analyzed ex vivo. tdTomato+ cells expressed cardiac myocyte markers, sarcomeric organization, excitation-contraction coupling, and action potentials characteristic of mature ventricular cardiac myocytes (tdTomato− cells). Reprogramming was associated with improvement of cardiac function, as analyzed by serial echocardiography. There was a time delayed and progressive improvement in fractional shortening and other measures of ventricular function, indicating that miR combo promotes functional recovery of damaged myocardium. The findings from this study further validate the potential utility of miRNA-mediated reprogramming as a therapeutic approach to promote cardiac regeneration following myocardial injury.