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Can Low Oxygen Unleash the Full Regenerative Capacity of the Adult Mammalian Heart?

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Review of  “Hypoxia induces heart regeneration in adult mice” from Nature by Stuart P. Atkinson

Recent studies have demonstrated that while the neonatal [1] and adult [2] mammalian heart can mount a regenerative response and produce new cardiomyocytes following myocardial infarction, this is insufficient to fully repair the damaged heart. The proliferation of existing cardiomyocytes serves as the source of new cells although this process remains highly sensitive to aerobic respiration-mediated oxidative DNA damage [3, 4].

With these findings in mind, a new study from the laboratories of Wataru Kimura and Hesham A. Sadek (University of Texas, USA) sought to assess the effect of low oxygen levels (hypoxemia) in the adult mouse heart. Their findings, published in Nature, suggest that low oxygen levels could represent a safe and effective means to unleash the full regenerative capacity of the adult mammalian heart [5].

In healthy 3-month-old mice, low oxygen conditions (7% O2 for 2 weeks) mediated a decrease in blood oxygen concentration and pH and a significant increase in blood CO2 levels. Cardiomyocytes themselves exhibited increased stabilization of hypoxia inducible factor 1 alpha subunit (Hif-1α) during early stages and later, decreased mitochondrial cristae density, cardiac mitochondrial DNA copy number, and levels of oxidative metabolism. This low mitochondrial activity also correlated with a significant decrease in reactive oxygen species (ROS) production, oxidative DNA damage, and DNA damage response (DDR). 

So what about cardiomyocyte proliferation? Excitingly, low oxygen conditions also led to an increase in heart weight to body weight ratio, a thickening of the myocardial wall, and an 8-fold increase in cardiomyocyte proliferation under normal conditions. Furthermore, following an induced myocardial infarction in the mouse heart, low oxygen conditions also permitted a heightened regenerative response leading to smaller fibrotic scar area and an improvement in systolic function.

As the authors note, low oxygen levels may seem a counterintuitive method to unleash the full regenerative capacity of the adult mammalian heart. However, the evidence presented in this exciting study suggests that the subsequent reduction in mitochondrial metabolism and ROS production is sufficient to induce cardiomyocyte proliferation in both healthy and injured hearts, leading to a heightened functional response to myocardial infarction.

References

  1. Porrello ER, Mahmoud AI, Simpson E, et al. Transient regenerative potential of the neonatal mouse heart. Science 2011;331:1078-1080.
  2. Senyo SE, Steinhauser ML, Pizzimenti CL, et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature 2013;493:433-436.
  3. Puente BN, Kimura W, Muralidhar SA, et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 2014;157:565-579.
  4. Kimura W, Xiao F, Canseco DC, et al. Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart. Nature 2015;523:226-230.
  5. Nakada Y, Canseco DC, Thet S, et al. Hypoxia induces heart regeneration in adult mice. Nature 2017;541:222-227.