Purpose

The neonatal mouse possesses a transient capacity for cardiac regeneration during the first few days of life. The regenerative response of neonatal mouse is primarily mediated by pre-existing cardiomyocyte (CM) proliferation, which has been identified as the primary source of myocardial regeneration. Postnatal 4-day-old (P4) mouse CMs appear to undergo a rapid transition from hyperplastic to hypertrophic growth and binucleation. By 7 days following birth this regenerative potential is lost which coincidently correspond with CM cell cycle arrest and binucleation. CCM2-like (Ccm2l) plays pivotal roles in cardiovascular development and cardiac growth, indicating a potential function in heart regeneration postnatally. The aim of this study was to determine the cardiac regeneration ability of P4 neonatal mouse using a novel and more reproducible injury model and to determine whether Ccm2l has any functional roles in heart repair following ischemic injury.

Methods

We performed a modified left anterior descending artery (LAD) ligation procedure on P4 mice to examine cardiac regenerative responses at different time points. Additionally, we generated an endothelial-specific Ccm2l gain-of-function transgenic mouse to determine the role of Ccm2l in neonatal cardiac regeneration.

Results

We found that the P4 mouse heart harbor a robust regenerative response after injury that was through the proliferation of pre-existing CMs but cardiac hypertrophy and subsequent remodeling was still evident 60 days after LAD ligation. Furthermore, we show that endothelial-specific overexpression of Ccm2l does not promote CM proliferation and heart repair after LAD ligation.

Conclusion

The neonatal heart at P4 harbors a robust but incomplete capacity for cardiac regeneration. Endothelial overexpression of Ccm2l has no effect on cardiac regeneration.

中文翻译：

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细胞周期退出限制了新生儿心肌细胞的再生潜力

目的

新生小鼠在生命的最初几天具有短暂的心脏再生能力。新生小鼠的再生反应主要由预先存在的心肌细胞 (CM) 增殖介导，已被确定为心肌再生的主要来源。出生后 4 天大 (P4) 的小鼠 CM 似乎经历了从增生到肥大生长和双核的快速转变。到出生后 7 天，这种再生潜力丧失，这与 CM 细胞周期停滞和双核化一致。CCM2 样 (Ccm2l) 在心血管发育和心脏生长中起关键作用，表明在出生后心脏再生中具有潜在功能。

方法

我们对 P4 小鼠进行了改良的左前降支 (LAD) 结扎手术，以检查不同时间点的心脏再生反应。此外，我们生成了内皮特异性 Ccm2l 功能获得性转基因小鼠，以确定 Ccm2l 在新生儿心脏再生中的作用。

结果

我们发现 P4 小鼠心脏在损伤后具有强大的再生反应，这是通过预先存在的 CM 的增殖，但在 LAD 结扎后 60 天，心脏肥大和随后的重塑仍然明显。此外，我们表明 Ccm2l 的内皮特异性过表达不会促进 LAD 结扎后的 CM 增殖和心脏修复。

结论

P4 处的新生儿心脏具有强大但不完整的心脏再生能力。Ccm2l 的内皮过表达对心脏再生没有影响。