重编程
Wnt信号通路
体内
细胞生物学
MEF2C公司
体外
心功能曲线
医学
癌症研究
转录因子
生物
细胞
内科学
信号转导
生物化学
心力衰竭
遗传学
基因
作者
Tamer Mohamed,Nicole R. Stone,Emily C. Berry,Ethan Radzinsky,Yu Huang,Karishma Pratt,Yen‐Sin Ang,Pengzhi Yu,Haixia Wang,Shibing Tang,Sergey Magnitsky,Sheng Ding,Kathryn N. Ivey,Deepak Srivastava
出处
期刊:Circulation
[Ovid Technologies (Wolters Kluwer)]
日期:2017-03-07
卷期号:135 (10): 978-995
被引量:191
标识
DOI:10.1161/circulationaha.116.024692
摘要
Background: Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells in situ represents a promising strategy for cardiac regeneration. A combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), can convert fibroblasts into induced cardiomyocyte-like cells, albeit with low efficiency in vitro. Methods: We screened 5500 compounds in primary cardiac fibroblasts to identify the pathways that can be modulated to enhance cardiomyocyte reprogramming. Results: We found that a combination of the transforming growth factor-β inhibitor SB431542 and the WNT inhibitor XAV939 increased reprogramming efficiency 8-fold when added to GMT-overexpressing cardiac fibroblasts. The small molecules also enhanced the speed and quality of cell conversion; we observed beating cells as early as 1 week after reprogramming compared with 6 to 8 weeks with GMT alone. In vivo, mice exposed to GMT, SB431542, and XAV939 for 2 weeks after myocardial infarction showed significantly improved reprogramming and cardiac function compared with those exposed to only GMT. Human cardiac reprogramming was similarly enhanced on transforming growth factor-β and WNT inhibition and was achieved most efficiently with GMT plus myocardin. Conclusions: Transforming growth factor-β and WNT inhibitors jointly enhance GMT-induced direct cardiac reprogramming from cardiac fibroblasts in vitro and in vivo and provide a more robust platform for cardiac regeneration.
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