Direct cardiac reprogramming holds great promise for regenerative medicine. We previously generated directly reprogrammed induced cardiomyocyte-like cells (iCMs) by overexpression of Gata4, Mef2c, and Tbx5 (GMT) using retrovirus vectors. However, integrating vectors pose risks associated with insertional mutagenesis and disruption of gene expression and are inefficient. Here, we show that Sendai virus (SeV) vectors expressing cardiac reprogramming factors efficiently and rapidly reprogram both mouse and human fibroblasts into integration-free iCMs via robust transgene expression. SeV-GMT generated 100-fold more beating iCMs than retroviral-GMT and shortened the duration to induce beating cells from 30 to 10 days in mouse fibroblasts. In vivo lineage tracing revealed that the gene transfer of SeV-GMT was more efficient than retroviral-GMT in reprogramming resident cardiac fibroblasts into iCMs in mouse infarct hearts. Moreover, SeV-GMT improved cardiac function and reduced fibrosis after myocardial infarction. Thus, efficient, non-integrating SeV vectors may serve as a powerful system for cardiac regeneration.

中文翻译：

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直接使用仙台病毒载体进行体内重编程可改善心肌梗塞后的心脏功能。

直接心脏重编程对于再生医学具有广阔的前景。我们先前使用逆转录病毒载体通过过表达Gata4，Mef2c和Tbx5（GMT）来生成直接重编程的诱导心肌样细胞（iCM）。然而，整合载体具有与插入诱变和基因表达破坏相关的风险，并且效率低下。在这里，我们显示仙台病毒（SeV）载体有效表达心脏重编程因子，并通过强大的转基因表达将小鼠和人类成纤维细胞快速重编程为无整合iCM。SeV-GMT产生比逆转录病毒-GMT多100倍的跳动iCM，并在小鼠成纤维细胞中将诱导跳动细胞的持续时间从30天缩短到10天。体内谱系追踪显示，SeV-GMT的基因转移比逆转录病毒-GMT更有效地将小鼠心肌梗死区的常驻心脏成纤维细胞重编程为iCM。此外，SeV-GMT可改善心肌梗死后的心脏功能并减少纤维化。因此，有效的，非整合的SeV载体可以充当用于心脏再生的强大系统。