Cardiogenesi diretta: nuove strategie molecolari per promuovere la rigenerazione cardiaca

Certain species of the animal kingdom, such as zebrafish, possess the amazing capability of efficiently regenerating their damaged heart, through the proliferation of pre-existing cardiomyocytes. In contrast, mammals sharply lose this innate capacity during early postnatal development. Consequently, cardiomyocytes lost after injuries in adult mammals are not regenerated, potentially leading to impaired cardiac function and, in severe cases, heart failure. This study aimed to investigate whether the regulation of specific growth factors or hormones during postnatal mammalian development contributes to the loss of cardiomyocyte regenerative potential.  Specifically, we identified growth factors with declining expression levels in early postnatal life in the mouse model and evaluated their mitogenic potential. Besides validating the pro-proliferative ability of previously identified regenerative growth factors, we unveiled novel factors stimulating cardiomyocyte cell cycle activity. Among them, BMP7, exhibited the most remarkable effects in triggering neonatal cardiomyocyte cell cycle activity, progression to the S-phase and division. Knockdown of Bmp7 in neonatal mouse cardiomyocytes in vitro and loss of function in zebrafish during cardiac regeneration in vivo reduced cardiomyocyte proliferation, suggesting that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in zebrafish hearts or delivery at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, boosted cardiomyocyte cycling. Mechanistically, we disclosed that BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and canonical SMAD5 and non-canonical ERK and AKT downstream signalling players mediate the BMP7 cardiomyocyte pro-regenerative effect. In parallel, we unveiled the crucial role of glucocorticoids (GCs) in restraining cardiomyocyte proliferation through activation of the glucocorticoid receptor (GR). Antagonization of the GC-GR axis was sufficient to boost neonatal murine cardiomyocyte proliferation and adult cardiomyocyte regeneration after myocardial infarction. Collectively, our data support BMP7 administration or GC-GR axis antagonization as promising therapeutical strategies to enhance cardiac regeneration in mammals after injury.