Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA.
The Krannert Institute of Cardiology, the Wells Center for Pediatric Research, and Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Dev Cell. 2018 Feb 26;44(4):433-446.e7. doi: 10.1016/j.devcel.2018.01.021.
Correlative evidence suggests that polyploidization of heart muscle, which occurs naturally in post-natal mammals, creates a barrier to heart regeneration. Here, we move beyond a correlation by demonstrating that experimental polyploidization of zebrafish cardiomyocytes is sufficient to suppress their proliferative potential during regeneration. Initially, we determined that zebrafish myocardium becomes susceptible to polyploidization upon transient cytokinesis inhibition mediated by dominant-negative Ect2. Using a transgenic strategy, we generated adult animals containing mosaic hearts composed of differentially labeled diploid and polyploid-enriched cardiomyocyte populations. Diploid cardiomyocytes outcompeted their polyploid neighbors in producing regenerated heart muscle. Moreover, hearts composed of equivalent proportions of diploid and polyploid cardiomyocytes failed to regenerate altogether, demonstrating that a critical percentage of diploid cardiomyocytes is required to achieve heart regeneration. Our data identify cardiomyocyte polyploidization as a barrier to heart regeneration and suggest that mobilizing rare diploid cardiomyocytes in the human heart will improve its regenerative capacity.
相关证据表明，心肌的多倍体化（在出生后的哺乳动物中自然发生）为心脏再生设置了障碍。在这里，我们通过证明斑马鱼心肌细胞的实验性多倍体化足以抑制其在再生过程中的增殖潜力，超越了相关性。最初，我们确定斑马鱼心肌在由显性失活的 Ect2 介导的短暂胞质分裂抑制下变得容易发生多倍体化。使用转基因策略，我们生成了包含由不同标记的二倍体和富含多倍体的心肌细胞群体组成的镶嵌心脏的成年动物。二倍体心肌细胞在产生再生心肌方面胜过其多倍体邻居。此外，由等量的二倍体和多倍体心肌细胞组成的心脏完全不能再生，表明需要有一定比例的二倍体心肌细胞才能实现心脏再生。我们的数据将心肌细胞多倍体化确定为心脏再生的障碍，并表明动员人类心脏中罕见的二倍体心肌细胞将提高其再生能力。
