Cell-based therapies for the treatment of myocardial infarction: lessons from cardiac regeneration and repair mechanisms in non-human vertebrates

Ischemic cardiomyopathy is the cardiovascular condition with the highest impact on the Western population. In mammals (humans included), prolonged ischemia in the ventricular walls causes the death of cardiomyocytes (myocardial infarction, MI). The loss of myocardial mass is soon compensated by the formation of a reparative, non-contractile fibrotic scar that ultimately affects heart performance. Despite the enormous clinical relevance of MI, no effective therapy is available for the long-term treatment of this condition. Moreover, since the human heart is not able to undergo spontaneous regeneration, many researchers aim at designing cell-based therapies that allow for the substitution of dead cardiomyocytes by new, functional ones. So far, the majority of such strategies rely on the injection of different progenitor/stem cells to the infarcted heart. These cardiovascular progenitors, which are expected to differentiate into cardiomyocytes de novo, seldom give rise to new cardiac muscle. In this context, the most important challenge in the field is to fully disclose the molecular and cellular mechanisms that could promote active myocardial regeneration after cardiac damage. Accordingly, we suggest that such strategy should be inspired by the unique regenerative and reparative responses displayed by non-human animal models, from the restricted postnatal myocardial regeneration abilities of the murine heart to the full ventricular regeneration of some bony fishes (e.g., zebrafish). In this review article, we will discuss about current scientific approaches to study cardiac reparative and regenerative phenomena using animal models.