Neuregulin1/ErbB4 Signaling Induces Cardiomyocyte Proliferation and Repair of Heart Injury
Neuregulin1/ErbB4 Signaling Induces Cardiomyocyte Proliferation and Repair of Heart Injury
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DOI：
10.1016/j.cell.2009.04.060
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发表时间：
2009-07-23
期刊：
影响因子：
64.5
通讯作者：
Kuehn, Bernhard
中科院分区：
文献类型：
--
作者：
Bersell, Kevin;Arab, Shima;Kuehn, Bernhard
许多器官依靠未分化的干细胞和祖细胞进行组织再生。分化的细胞本身是否有助于细胞替代和组织再生是一个有争议的问题。在这里，我们表明，分化的心肌细胞，心肌细胞，可以诱导增殖和再生。我们确定了一个潜在的分子机制，控制这一过程，涉及生长因子神经调节蛋白1（NRG 1）和酪氨酸激酶受体，ErbB 4。NRG 1诱导单核而非双核心肌细胞分裂。在体内，ErbB 4基因失活减少心肌细胞增殖，而ErbB 4表达增加则增强心肌细胞增殖。在成年小鼠中注射NRG 1可诱导心肌细胞周期活性，促进心肌再生，从而改善心肌梗死后的功能。未分化的祖细胞没有NRG 1诱导的心肌细胞增殖。因此，增加NRG 1/ErbB 4信号通路的活性可能提供促进心肌再生的分子策略。
Many organs rely on undifferentiated stem and progenitor cells for tissue regeneration. Whether differentiated cells themselves can contribute to cell replacement and tissue regeneration is a controversial question. Here, we show that differentiated heart muscle cells, cardiomyocytes, can be induced to proliferate and regenerate. We identify an underlying molecular mechanism for controlling this process that involves the growth factor neuregulin1 (NRG1) and its tyrosine kinase receptor, ErbB4. NRG1 induces mononucleated, but not binucleated, cardiomyocytes to divide. In vivo, genetic inactivation of ErbB4 reduces cardiomyocyte proliferation, whereas increasing ErbB4 expression enhances it. Injecting NRG1 in adult mice induces cardiomyocyte cell-cycle activity and promotes myocardial regeneration, leading to improved function after myocardial infarction. Undifferentiated progenitor cells did not contribute to NRG1-induced cardiomyocyte proliferation. Thus, increasing the activity of the NRG1/ErbB4 signaling pathway may provide a molecular strategy to promote myocardial regeneration.