Could heart regeneration one day be possible in humans? Given the prevalence of heart-related diseases worldwide, answering this question could have considerable consequences for human health-span. Myocardial infarction can result in the death of up to 1 billion cardiomyocytes. Cell death is followed by the formation of a permanent scar through fibrosis, which impairs cardiac function and often leads to chronic heart failure. Unlike regenerative mammalian organs such as the liver, the heart has been traditionally viewed as a terminally differentiated organ with limited cell proliferative capacity. Therefore, historically, the treatment of heart conditions resulting from cardiac injury has focused primarily on damage control and symptom management.

The discovery in the early 2000s by Kenneth Poss and colleagues that lower vertebrates such as zebrafish and salamanders could regenerate their hearts throughout their whole lives sparked interest in exploring whether similar mechanisms exist at certain developmental points in mammals. In 2011, Enzo Porrello and colleagues shared groundbreaking research showing that mice 1 day old can regenerate their hearts after myocardial injury (removal of the heart apex), but this capacity is rapidly lost by day 7 after birth, revealing the existence of a transient regenerative window. Importantly, the study showed that heart regeneration in neonatal mice occurred in a similar fashion to that in zebrafish: through cardiomyocyte proliferation with minimal hypertrophy and fibrosis. Genetic fate mapping analyses revealed that the new cardiomyocytes in the regenerative region originated from pre-existing cardiomyocytes. Remarkably, 2 months after surgery, the regenerated ventricular apex had normal systolic function. Thus, this study was the first-ever account of complete mammalian heart regeneration.