Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity.
Notch Inhibition Enhances Cardiac Reprogramming by Increasing MEF2C Transcriptional Activity.
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DOI：
10.1016/j.stemcr.2017.01.025
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发表时间：
2017-03-14
影响因子：
5.9
通讯作者：
Olson EN
中科院分区：
文献类型：
--
作者：
Abad M;Hashimoto H;Zhou H;Morales MG;Chen B;Bassel-Duby R;Olson EN
成纤维细胞转化为功能性心肌细胞是心肌梗死后恢复心脏功能的潜在手段，但迄今为止该过程仍然效率低下，并且对其分子机制知之甚少。在这里，我们展示了 DAPT（一种经典的 Notch 抑制剂）通过转录因子 GATA4、HAND2、MEF2C 和 TBX5 增强小鼠成纤维细胞向诱导性心肌细胞的转化。 DAPT 与 AKT 激酶配合，进一步增强这一过程，实现高达 70% 的转化效率。此外，DAPT 促进特定心肌细胞特征的获得，显着增加钙通量、肌节结构和自发跳动细胞的数量。转录组分析表明 DAPT 诱导与肌肉发育、分化和兴奋-收缩耦合相关的遗传程序。从机制上讲，DAPT 增加转录因子 MEF2C 与心脏结构基因启动子区域的结合。这些发现为重编程过程提供了机制上的见解，并可能对心脏再生疗法具有重要意义。 Notch 激活是 GHMT 诱导的心脏细胞重编程的障碍 DAPT 阻断 Notch 可以改善 GHMT 诱导的心脏重编程 DAPT 增加 GHMT 重编程中的肌节组织、钙通量和搏动 DAPT 增强 GHMT 重编程中 MEF2C 的转录活性 在这篇文章中，Olson 及其同事表明，Notch 信号传导激活是心脏细胞重编程的关键障碍。 DAPT（一种 γ 分泌酶抑制剂）阻断 Notch 信号传导，通过增加钙通量、肌节结构和搏动来增强成纤维细胞向心肌细胞的转化。从机制上讲，Notch 抑制增强了心肌转录因子 MEF2C 的转录活性，从而增强心脏基因的表达。
Conversion of fibroblasts into functional cardiomyocytes represents a potential means of restoring cardiac function after myocardial infarction, but so far this process remains inefficient and little is known about its molecular mechanisms. Here we show that DAPT, a classical Notch inhibitor, enhances the conversion of mouse fibroblasts into induced cardiac-like myocytes by the transcription factors GATA4, HAND2, MEF2C, and TBX5. DAPT cooperates with AKT kinase to further augment this process, resulting in up to 70% conversion efficiency. Moreover, DAPT promotes the acquisition of specific cardiomyocyte features, substantially increasing calcium flux, sarcomere structure, and the number of spontaneously beating cells. Transcriptome analysis shows that DAPT induces genetic programs related to muscle development, differentiation, and excitation-contraction coupling. Mechanistically, DAPT increases binding of the transcription factor MEF2C to the promoter regions of cardiac structural genes. These findings provide mechanistic insights into the reprogramming process and may have important implications for cardiac regeneration therapies. Notch activation is a barrier for GHMT-induced cardiac cell reprogramming Notch blockade by DAPT improves GHMT-induced cardiac reprogramming DAPT increases sarcomere organization, calcium flux, and beating in GHMT reprogramming DAPT enhances transcriptional activity of MEF2C in GHMT reprogramming In this article, Olson and colleagues show that Notch signaling activation is a critical barrier for cardiac cell reprogramming. Notch signaling blockade by DAPT, a γ-secretase inhibitor, enhances fibroblast conversion to cardiomyocytes by increasing calcium flux, sarcomere structure, and beating. Mechanistically, Notch inhibition enhances the transcriptional activity of the cardiogenic transcription factor MEF2C, thereby enhancing expression of cardiac genes.