Direct Reprogramming of Human Fibroblasts toward a Cardiomyocyte-like State

被引:271
作者
Fu, Ji-Dong [1 ,2 ,3 ,4 ]
Stone, Nicole R. [1 ,2 ,3 ,4 ]
Liu, Lei [1 ]
Spencer, C. Ian [1 ,3 ,4 ]
Qian, Li [1 ,2 ]
Hayashi, Yohei [1 ]
Delgado-Olguin, Paul [1 ]
Ding, Sheng [1 ,2 ,6 ]
Bruneau, Benoit G. [1 ,2 ,3 ,5 ]
Srivastava, Deepak [1 ,2 ,3 ,4 ]
机构
[1] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA
[2] Roddenberry Ctr Stem Cell Biol & Med Gladstone, San Francisco, CA 94158 USA
[3] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94158 USA
[4] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA
[5] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA
[6] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA
来源
STEM CELL REPORTS | 2013年 / 1卷 / 03期
关键词
CARDIAC TRANSCRIPTION FACTORS; PLURIPOTENT STEM-CELLS; DEFINED FACTORS; HEART; EXPRESSION; INDUCTION; MYOCARDIN; COFACTOR; FOG-2; TBX5;
D O I
10.1016/j.stemcr.2013.07.005
中图分类号
Q813 [细胞工程];
学科分类号
摘要
Direct reprogramming of adult somatic cells into alternative cell types has been shown for several lineages. We previously showed that GATA4, MEF2C, and TBX5 (GMT) directly reprogrammed nonmyocyte mouse heart cells into induced cardiomyocyte-like cells (iCMs) in vitro and in vivo. However, GMT alone appears insufficient in human fibroblasts, at least in vitro. Here, we show that GMT plus ESRRG and MESP1 induced global cardiac gene-expression and phenotypic shifts in human fibroblasts derived from embryonic stem cells, fetal heart, and neonatal skin. Adding Myocardin and ZFPM2 enhanced reprogramming, including sarcomere formation, calcium transients, and action potentials, although the efficiency remained low. Human iCM reprogramming was epigenetically stable. Furthermore, we found that transforming growth factor beta signaling was important for, and improved the efficiency of, human iCM reprogramming. These findings demonstrate that human fibroblasts can be directly reprogrammed toward the cardiac lineage, and lay the foundation for future refinements in vitro and in vivo.
引用
收藏
页码:235 / 247
页数:13
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