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.

中文翻译：

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BMP7促进心肌细胞再生

斑马鱼在严重损伤后具有显着的终生心脏再生能力，而哺乳动物在出生后早期发育过程中失去了先天的心脏再生能力。本研究旨在探讨哺乳动物出生后发育过程中生长因子产生的减少是否导致心肌细胞退出细胞周期和心脏再生能力降低。我们在小鼠模型中鉴定了出生后早期表达水平下降的生长因子，并在体外评估了这些因子对新生小鼠原代心肌细胞的促增殖能力。我们的研究结果证实了之前报道的 NRG1、IL1b、RANKL、IGF2 和 IL6 的促增殖作用，同时还确定了新型潜在的促再生生长因子。他们之中，BMP7表现出最显着的功效。Bmp7 敲低干扰了培养物中新生小鼠心肌细胞的增殖，而成年 bmp7 突变斑马鱼在心脏再生过程中表现出心肌细胞增殖减少，表明 Bmp7 对于小鼠和斑马鱼心脏再生阶段的心肌细胞增殖至关重要。相反，bmp7 过表达足以促进再生斑马鱼心脏中的心肌细胞循环，而 BMP7 给药可刺激出生后第 7 天（此时心肌细胞停止增殖）的小鼠心肌细胞循环，并增强成年小鼠心肌梗死后的体内心肌细胞再生。从机制上讲，BMP7诱导的增殖是由I型BMP受体BMPR1A和ACVR1以及II型受体ACVR2A和BMPR2介导的。下游信号传导涉及 SMAD5、ERK 和 AKT。总之，BMP7 的施用有望成为心脏损伤后刺激心脏再生的策略。