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Hypoxia induces heart regeneration in adult mice
来源:2 2 2 | N A T U R E | V O L 5 4 1 | 1 2 j A N U A R y 2 0 1 7 | 作者:pmo597dc1 | 时间 :2017-12-04 | 578 次浏览 | 分享到:

2 2 2 | N A T U R E | V O L 5 4 1 | 1 2 j A N U A R y 2 0 1 7
Abstract

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 myocardium1, and the adult heart is capable of modest self-renewal2,3. In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobicrespiration-mediated oxidative DNA damage4,5. 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.

 

解读:肌细胞自我更新主要是通过内源性细胞的增殖实现,并且其增殖受到有氧呼吸介导的DNA氧化损伤所调控。作者推测具有抑制有氧呼吸和减轻氧化DNA损伤作用的系统性低氧血症,有可能在成年哺乳动物中诱导心肌细胞的增殖。在本文中,通过逐渐降低氧分压,按1%的梯度进行递减,并将最终氧浓度控制在7%,保持两周时间,可以抑制氧化代谢、降低活性氧自由基水平和DNA氧化损伤,并激活心肌细胞的有丝分裂。有趣的是,在诱导心肌梗死后,保持低氧血症1周时间,可以显着促进组织再生反应,降低心肌纤维化,并增强左心室收缩功能。 最后,通过遗传示踪的手段证明新生的心肌来自于已经存在的心肌细胞。综上,低氧可以促进成年哺乳动物内源心肌细胞的再生能力,从而展现了低氧在再生医学中的潜在治疗意义。