Pontis, F. | Search bioRxiv

bioRxiv2023

BMP7 promotes cardiomyocyte regeneration

Zebrafish has a remarkable and lifelong ability for cardiac regeneration after severe damage, whereas mammals lose their innate capacity for heart regeneration during early postnatal development. This study aimed to investigate whether the decreased production of growth factors during postnatal mammalian development contributes to the exit of cardiomyocytes from the cell cycle and the reduction in cardiac regenerative ability. We identified growth factors with declining expression levels during early postnatal life in the mouse model and assessed the pro-proliferative ability of these factors on neonatal murine primary cardiomyocytes in vitro. Our findings confirmed the previously reported pro-proliferative effects of NRG1, IL1b, RANKL, IGF2 and IL6, while also identifying novel potential pro-regenerative growth factors. Among them, BMP7 exhibited the most pronounced efficacy. Bmp7 knockdown interfered with the proliferation of neonatal mouse cardiomyocytes in culture and adult bmp7 mutant zebrafish displayed reduced cardiomyocyte proliferation during heart regeneration, indicating that Bmp7 is crucial for cardiomyocyte proliferation in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression was sufficient to boost cardiomyocyte cycling in regenerating zebrafish hearts, while BMP7 administration stimulated mouse cardiomyocyte cycling at postnatal-day-7, when cardiomyocytes ceased to proliferate, and enhanced cardiomyocyte regeneration in vivo in adult mice following myocardial infarction. Mechanistically, BMP7-induced proliferation was mediated by type I BMP receptors BMPR1A and ACVR1, and type II receptors ACVR2A and BMPR2. Downstream signalling involved SMAD5, ERK and AKT. In conclusion, the administration of BMP7 holds promise as a strategy to stimulate heart regeneration following cardiac injury.

molecular biology↗

bioRxiv2020

Glucocorticoid Receptor ablation promotes cardiac regeneration by hampering cardiomyocyte terminal differentiation

In mammals, glucocorticoid levels rise dramatically shortly before birth and prepare the foetus for post-natal life by promoting the maturation of the lungs and other organs. However, their impact on cardiac postnatal growth and regenerative plasticity is unknown. Here, we demonstrate that exposure to endogenous glucocorticoids facilitates cell cycle exit and reduces the proliferation of neonatal cardiomyocytes. This cytostatic activity is shared by several synthetic glucocorticoid receptor (GR) agonists routinely used in clinical settings. We also observed that GR levels increase in cardiomyocytes during early post-natal development. Importantly, in vivo cardiomyocyte-specific GR ablation delayed the transition from hyperplastic (increase in cell number) to hypertrophic (increase in cell size) growth. Further, GR ablation partially impaired cardiomyocyte maturation, reducing myofibrils-mitochondria organization along with the expression of genes involved in fatty acid metabolism, mitochondrial respiration and energy transfer from mitochondria to the cytosol. Finally, we show increased cardiomyocyte proliferation in GR ablated juvenile and adult cardiomyocytes in response to myocardial infarction in vivo, thus promoting cardiac tissue regeneration. We suggest that GR antagonization could serve as a strategy for heart regeneration based on endogenous cardiomyocyte renewal.

cell biology↗