Hypoxia induces heart regeneration in adult mice
Hypoxia induces heart regeneration in adult mice
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DOI：
10.1038/nature20173
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发表时间：
2017-01-12
期刊：
影响因子：
64.8
通讯作者：
Sadek, Hesham A.
中科院分区：
文献类型：
--
作者：
Nakada, Yuji;Canseco, Diana C.;Sadek, Hesham A.
成年哺乳动物的心脏在心肌细胞丧失后不能再生，这是心肌病持续和严重影响的基础。最近，已经清楚的是，哺乳动物的心脏不是一个有丝分裂后的器官。例如，新生儿心脏能够再生失去的心肌（1），成人心脏能够适度自我更新（2，3）。在这两种情况下，心肌细胞更新通过预先存在的心肌细胞的增殖发生，并受有氧呼吸介导的氧化DNA损伤的调节（4，5）。因此，我们推断通过诱导全身低氧血症来抑制有氧呼吸可以减轻氧化性DNA损伤，从而诱导成年哺乳动物的心肌细胞增殖。在这里，我们报告说，在小鼠中，逐渐暴露于严重的全身性低氧血症，其中吸入的氧气逐渐减少1%，并保持在7%的2周，结果在抑制氧化代谢，减少活性氧的产生和氧化DNA损伤，并重新激活心肌细胞有丝分裂。值得注意的是，我们发现，暴露于低氧血症诱导心肌梗死后1周诱导一个强大的再生反应，减少心肌纤维化和改善左心室收缩功能。遗传基因图谱分析证实，新形成的心肌是来自预先存在的心肌细胞。这些结果表明，成年哺乳动物心脏的内源性再生特性可以通过暴露于逐渐全身性低氧血症而重新激活，并突出了低氧在再生医学中的潜在治疗作用。
The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium(1), and the adult heart is capable of modest self-renewal(2,3). In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage(4,5). Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that, in mice, gradual exposure to severe systemic hypoxaemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Notably, we find that exposure to hypoxaemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Genetic fate-mapping analysis confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.