Hippo signaling impedes adult heart regeneration
Hippo signaling impedes adult heart regeneration
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DOI：
10.1242/dev.102798
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发表时间：
2013-12-01
期刊：
影响因子：
4.6
通讯作者：
Martin, James F.
中科院分区：
文献类型：
--
作者：
Heallen, Todd;Morikawa, Yuka;Martin, James F.
在美国，由于缺血性心脏病后心肌细胞丢失导致的心力衰竭是主要的死亡原因，这在很大程度上是因为心肌再生不良。防止哺乳动物心肌细胞再生的内源性机制知之甚少。Hippo信号传导是一种古老的器官大小控制途径，是一种抑制发育中心肌细胞增殖的激酶级联反应，但尚未在出生后或完全成熟的成年心肌细胞中进行研究。在这里，我们研究了成年心肌细胞更新和再生中的Hippo信号。我们发现，无应激海马缺陷的成年小鼠心肌细胞重新进入细胞周期，并进行胞质分裂。此外，Hippo缺乏增强心肌细胞再生，在成人心肌梗死后以及在出生后第八天（P8）心尖切除术和P8心肌梗死后具有功能恢复。在受损的心脏中，Hippo突变型心肌细胞也具有升高的增殖。我们的研究结果表明，Hippo信号是一个内源性阻遏成年心肌细胞更新和再生。在人类疾病中靶向Hippo通路可能有助于治疗心脏病。
Heart failure due to cardiomyocyte loss after ischemic heart disease is the leading cause of death in the United States in large part because heart muscle regenerates poorly. The endogenous mechanisms preventing mammalian cardiomyocyte regeneration are poorly understood. Hippo signaling, an ancient organ size control pathway, is a kinase cascade that inhibits developing cardiomyocyte proliferation but it has not been studied postnatally or in fully mature adult cardiomyocytes. Here, we investigated Hippo signaling in adult cardiomyocyte renewal and regeneration. We found that unstressed Hippo-deficient adult mouse cardiomyocytes re-enter the cell cycle and undergo cytokinesis. Moreover, Hippo deficiency enhances cardiomyocyte regeneration with functional recovery after adult myocardial infarction as well as after postnatal day eight (P8) cardiac apex resection and P8 myocardial infarction. In damaged hearts, Hippo mutant cardiomyocytes also have elevated proliferation. Our findings reveal that Hippo signaling is an endogenous repressor of adult cardiomyocyte renewal and regeneration. Targeting the Hippo pathway in human disease might be beneficial for the treatment of heart disease.