Using Hypoxia to Induce Heart Regeneration in Mice
The heart is one of the least regenerative organs in mammals, and the scientific community has for some time put in considerable effort to search for viable strategies to overcome this limitation. While much of the focus of this research is on cell therapies, such as the use of stem cell transplants, there are other possible approaches. The researchers here uncover an interesting possibility involving decreased oxygen intake, or hypoxia. It is known that mild hypoxia induces many of the same beneficial responses, such as increased cellular repair and maintenance, as are produced by calorie restriction. That seems to be enough to generate a greater regenerative response in heart tissue as well:
The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the devastating impact 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, and the adult heart is capable of modest self-renewal. In both these scenarios, cardiomyocyte renewal occurs through proliferation of pre-existing cardiomyocytes, and is regulated by aerobic respiration-mediated oxidative DNA damage. Therefore, we reasoned that systemic hypoxemia inhibits aerobic respiration and alleviates oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals.
Here we report that gradual exposure to severe systemic hypoxemia, where inspired oxygen is gradually decreased by 1% and maintained at 7% for two weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species (ROS) production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Intriguingly, we found that exposure to hypoxemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Finally, genetic fate mapping confirmed 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 hypoxemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.