In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes
In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes
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DOI：
10.1038/nature11044
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发表时间：
2012-05-31
期刊：
影响因子：
64.8
通讯作者：
Srivastava, Deepak
中科院分区：
文献类型：
--
作者：
Qian, Li;Huang, Yu;Srivastava, Deepak
将成体细胞重编程为多能细胞或直接重编程为替代的成体细胞类型为再生医学带来了巨大的希望。我们以前报道过，心脏成纤维细胞，这代表了50%的细胞在哺乳动物的心脏，可以直接重编程为成人心肌样细胞在体外加入Gata4，Mef2c和Tbx5（GMT）。在这里，我们使用遗传谱系追踪表明，在小鼠心脏中的居民非心肌细胞可以重新编程为心肌样细胞在体内的冠状动脉结扎后，通过局部交付GMT。诱导的心肌细胞变成双核，组装肌节，并有心肌样基因表达。对单个细胞的分析揭示了心室心肌细胞样动作电位，在电刺激下跳动，以及电耦合的证据。在冠状动脉结扎后3个月内，体内给予GMT可减少梗死面积并适度减轻心功能不全。递送促血管生成和成纤维细胞活化肽，胸腺素β 4，沿着GMT，导致瘢痕面积和心脏功能的进一步改善。这些发现表明，心脏成纤维细胞可以在其天然环境中重编程为心肌样细胞，用于潜在的再生目的。
The reprogramming of adult cells into pluripotent cells or directly into alternative adult cell types holds great promise for regenerative medicine. We reported previously that cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be directly reprogrammed to adult cardiomyocyte-like cells in vitro by the addition of Gata4, Mef2c and Tbx5 (GMT). Here we use genetic lineage tracing to show that resident non-myocytes in the murine heart can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of GMT after coronary ligation. Induced cardiomyocytes became binucleate, assembled sarcomeres and had cardiomyocyte-like gene expression. Analysis of single cells revealed ventricular cardiomyocyte-like action potentials, beating upon electrical stimulation, and evidence of electrical coupling. In vivo delivery of GMT decreased infarct size and modestly attenuated cardiac dysfunction up to 3 months after coronary ligation. Delivery of the pro-angiogenic and fibroblast-activating peptide, thymosin beta 4, along with GMT, resulted in further improvements in scar area and cardiac function. These findings demonstrate that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells in their native environment for potential regenerative purposes.