Heart Regeneration: An Evolutionary Tale
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Lower vertebrates like urodele amphibians and teleost fish retain a robust cardiac regenerative capacity throughout their life, a phenomenon that is mediated through the proliferation of pre-existing cardiomyocytes. The adult mammalian heart lacks any meaningful endogenous regenerative response following injury. However, embryonic mammalian cardiomyocytes are proliferative and exit the cell cycle shortly after birth. The question of whether the mammalian heart lacks this regenerative potential or is lost early after birth was not clear. We were able to show that the hearts of 1-day-old mice regenerated following partial surgical resection of the neonatal heart, a phenomenon that is lost within a week after birth. Thus, for a brief period after birth, the mammalian heart appears to have the capacity to regenerate due to the proliferative competency of cardiomyocytes. However, one major unresolved question was whether the neonatal mouse heart could also regenerate in response to myocardial ischemia, the most common antecedent of heart failure in humans. To examine this question, we induced myocardial infarction (MI) in 1-day-old mice by ligating the left anterior descending coronary artery, and found that this results in extensive myocardial necrosis and systolic dysfunction. Remarkably, the neonatal mouse heart mounted a robust regenerative response, through proliferation of pre-existing cardiomyocytes, which resulted in full functional recovery within 21 days. Moreover, we were able to demonstrate that the neonatal heart is capable of regeneration following mild, but not severe cryoinjury. Therefore, our work identifies a short period of time after birth where the mammalian heart is capable of regeneration following various types of injury. To unravel the molecular mechanisms that regulate the regenerative capacity of the neonatal mammalian heart, we determined that the miR-15 family regulates neonatal heart regeneration through inducing post-natal cardiomyocyte cell cycle arrest. Moreover, inhibition of the miR-15 family at an early post-natal age until adulthood induces cardiomyocyte proliferation in the adult heart and improves left ventricular systolic function following MI. In conclusion, our findings indicate that the mammalian heart harbors a robust regenerative capacity for a short period of time after birth, mediated by proliferation of pre-existing cardiomyocytes, and that the miR-15 family is an important regulator of post-natal cardiomyocytes cell cycle arrest.