Functional screening identifies miRNAs inducing cardiac regeneration
Functional screening identifies miRNAs inducing cardiac regeneration
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DOI：
10.1038/nature11739
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发表时间：
2012-12-20
期刊：
影响因子：
64.8
通讯作者：
Giacca, Mauro
中科院分区：
文献类型：
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作者：
Eulalio, Ana;Mano, Miguel;Giacca, Mauro
在哺乳动物中，胚胎发育期间心脏的增大主要取决于心肌细胞数量的增加。然而，出生后不久，心肌细胞停止增殖，并且通过现有心肌细胞的肥大性增大而发生心肌的进一步生长。由于成年期心肌细胞的更新很少，因此通过心肌再生修复心脏损伤非常有限。在这里，我们表明，外源性管理选定的microRNAs（miRNAs）显着刺激心肌细胞增殖，促进心脏修复。我们使用全基因组miRNA文库对促进新生心肌细胞增殖的人类miRNA进行了高内容显微镜、高通量功能筛选。40种miRNAs在新生小鼠和大鼠心肌细胞中强烈增加DNA合成和胞质分裂。进一步选择这些miRNA中的两种（hsa-miR-590和hsa-miR-199 a）用于测试，并且显示出促进离体成年心肌细胞的细胞周期再进入，并促进新生和成年动物中的心肌细胞增殖。在小鼠心肌梗死后，这些miRNAs刺激了显著的心脏再生和心脏功能参数的几乎完全恢复。所鉴定的miRNAs对于治疗心肌细胞损失引起的心脏病理具有很大的希望。
In mammals, enlargement of the heart during embryonic development is primarily dependent on the increase in cardiomyocyte numbers. Shortly after birth, however, cardiomyocytes stop proliferating and further growth of the myocardium occurs through hypertrophic enlargement of the existing myocytes. As a consequence of the minimal renewal of cardiomyocytes during adult life, repair of cardiac damage through myocardial regeneration is very limited. Here we show that the exogenous administration of selected microRNAs (miRNAs) markedly stimulates cardiomyocyte proliferation and promotes cardiac repair. We performed a high-content microscopy, high-throughput functional screening for human miRNAs that promoted neonatal cardiomyocyte proliferation using a whole-genome miRNA library. Forty miRNAs strongly increased both DNA synthesis and cytokinesis in neonatal mouse and rat cardiomyocytes. Two of these miRNAs (hsa-miR-590 and hsa-miR-199a) were further selected for testing and were shown to promote cell cycle re-entry of adult cardiomyocytes ex vivo and to promote cardiomyocyte proliferation in both neonatal and adult animals. After myocardial infarction in mice, these miRNAs stimulated marked cardiac regeneration and almost complete recovery of cardiac functional parameters. The miRNAs identified hold great promise for the treatment of cardiac pathologies consequent to cardiomyocyte loss.