Abstract：
Factors responsible for cardiomyocyte proliferation could serve as potential therapeutics to stimulate endogenous myocardial regeneration following insult, such as ischemic injury. A previously published forward genetics approach on cardiomyocyte cell cycle and ploidy led us to the transcription factor, RUNX1. Here, we examine the effect of Runx1 on cardiomyocyte cell cycle during postnatal development and cardiac regeneration using cardiomyocyte-specific gain- and loss-of-function mouse models. RUNX1 is expressed in cardiomyocytes during early postnatal life, decreases to negligible levels by 3 weeks of age, and increases upon myocardial injury, all consistent with observed rates of cardiomyocyte cell cycle activity. Loss of Runx1 transiently stymied cardiomyocyte cell cycle activity during normal postnatal development, a result that corrected itself and did not extend to the context of neonatal heart regeneration. On the other hand, cardiomyocyte-specific Runx1 overexpression resulted in an expansion of diploid cardiomyocytes in uninjured hearts and expansion of 4N cardiomyocytes in the context of neonatal cardiac injury, suggesting Runx1 overexpression is sufficient to induce cardiomyocyte cell cycle responses. Persistent overexpression of Runx1 for >1 month continued to promote cardiomyocyte cell cycle activity resulting in substantial hyperpolyploidization (≥8N DNA content). This persistent cell cycle activation was accompanied by ventricular dilation and adverse remodeling, raising the concern that continued cardiomyocyte cell cycling can have detrimental effects.
摘要：
导致心肌细胞增殖的因素可以作为刺激损伤后内源性心肌再生的潜在疗法。如缺血性损伤。先前发表的关于心肌细胞细胞周期和倍性的正向遗传学方法使我们找到了转录因子，RUNX1.这里,我们使用心肌细胞特异性功能增益和功能丧失小鼠模型研究了Runx1对出生后发育和心脏再生过程中心肌细胞细胞周期的影响.RUNX1在出生后早期的心肌细胞中表达，到3周龄时下降到可忽略不计的水平，并在心肌损伤时增加，所有与观察到的心肌细胞细胞周期活性速率一致。在正常的出生后发育过程中，Runx1的丧失暂时阻碍了心肌细胞的细胞周期活性，这一结果自我纠正，并没有延伸到新生儿心脏再生的背景下。另一方面,在新生儿心脏损伤的情况下，心肌细胞特异性Runx1过表达导致未受伤心脏中二倍体心肌细胞的扩增和4N心肌细胞的扩增，表明Runx1过表达足以诱导心肌细胞细胞周期反应。Runx1持续过表达>1个月持续促进心肌细胞细胞周期活性，导致大量超多倍体化（≥8NDNA含量）。这种持续的细胞周期激活伴随着心室扩张和不良重塑，引起人们对持续心肌细胞循环可能产生有害影响的担忧。
