The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion
The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion
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DOI：
10.1242/dev.068601
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发表时间：
2011-08-15
期刊：
影响因子：
4.6
通讯作者：
Poss, Kenneth D.
中科院分区：
文献类型：
--
作者：
Wang, Jinhu;Panakova, Daniela;Poss, Kenneth D.
斑马鱼等低等脊椎动物心脏再生的自然模型是基于侵入性手术，造成大小有限的机械损伤。在这里，我们在斑马鱼中创建了一个遗传细胞消融模型，该模型有助于诱导破坏高百分比的心肌细胞。细胞特异性消耗超过60%的心室心肌，引发了部分心室切除术后未观察到的心力衰竭体征，包括动物运动耐量降低和应激源环境下的猝死。大量心肌丧失激活了内皮细胞、免疫细胞、心外膜细胞和血管细胞的强大细胞和分子反应。被破坏的心肌细胞在几天内完全再生，恢复心脏解剖学，生理学和性能。再生肌来源于获得去分化的超微结构和电生理特征并经历旺盛增殖的备用心肌细胞。我们的研究表明，心肌细胞的遗传耗竭，即使是在如此极端的水平，以引起心力衰竭的迹象，可以逆转自然再生能力在低等脊椎动物，如斑马鱼。
Natural models of heart regeneration in lower vertebrates such as zebrafish are based on invasive surgeries causing mechanical injuries that are limited in size. Here, we created a genetic cell ablation model in zebrafish that facilitates inducible destruction of a high percentage of cardiomyocytes. Cell-specific depletion of over 60% of the ventricular myocardium triggered signs of cardiac failure that were not observed after partial ventricular resection, including reduced animal exercise tolerance and sudden death in the setting of stressors. Massive myocardial loss activated robust cellular and molecular responses by endocardial, immune, epicardial and vascular cells. Destroyed cardiomyocytes fully regenerated within several days, restoring cardiac anatomy, physiology and performance. Regenerated muscle originated from spared cardiomyocytes that acquired ultrastructural and electrophysiological characteristics of de-differentiation and underwent vigorous proliferation. Our study indicates that genetic depletion of cardiomyocytes, even at levels so extreme as to elicit signs of cardiac failure, can be reversed by natural regenerative capacity in lower vertebrates such as zebrafish.