Cianflone, E.; Marino, F.; Scalise, M.; Smith, A. J.; Siracusa, C.; Pagano, L.; Quercia, C.; Salerno, N.; Di Costanzo, A.; Canino, G.; De Angelis, A.; Ellison-Hughes, G. M.; Urbanek, K.; Nadal-Ginard, B.; Torella, D.

A central unresolved and highly contested question in cardiac biology is whether the adult mammalian heart, believed to have a very limited endogenous cardiomyocyte (CM) regenerative capacity, can be coaxed into an effective regenerative response after acute CM loss. Using TgMyh6MCM:R26stop-DTA mice, we show that selective diffuse ablation of ~15% of left ventricular CMs causes acute heart failure but is followed by complete structural and functional recovery within 28 days. Recovery is accomplished by robust generation of new mononucleated CMs, replacing ~1/10 of the left ventricular CM compartment. This CM regeneration is produced by the activation of resident cardiac stem cells (CSCs), which exit quiescence, proliferate, produce new CMs, and subsequently return to quiescence. Depletion of the putative CSCs blocks repair, whereas transplantation of either clonogenic or primary CSCs through the systemic circulation fully restores myocardial regeneration and function, establishing that the CSCs home, nest and differentiate in the damaged myocardium and, therefore, are the main effectors of regeneration in this setting. Mechanistically, we show that miR-221-dependent repression of p57 governs the transition from quiescence--to activation--to differentiation--to quiescence of the CSCs, defining a reversible regulatory program which, under the proper conditions, endows the adult myocardium with robust CM regenerative competence.