Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Development. 2011 Aug;138(16):3421-30. doi: 10.1242/dev.068601. Epub 2011 Jul 13.
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.
在较低等的脊椎动物中，如斑马鱼，自然的心脏再生模型是基于会造成机械损伤的侵入性手术，而这种损伤的大小是有限的。在这里，我们在斑马鱼中创建了一种遗传细胞消融模型，该模型可以诱导破坏高比例的心肌细胞。心室心肌的特异性耗竭超过 60%，会引发心力衰竭的迹象，而在部分心室切除后则不会观察到这些迹象，包括动物运动耐受力降低和在应激条件下突然死亡。大量的心肌损失激活了心内膜、免疫、心外膜和血管细胞的强大的细胞和分子反应。受损的心肌细胞在几天内完全再生，恢复了心脏的解剖、生理和功能。再生的肌肉来源于未受损的心肌细胞，这些细胞获得了去分化的超微结构和电生理特征，并经历了强烈的增殖。我们的研究表明，即使在低等脊椎动物如斑马鱼中，通过自然的再生能力，也可以逆转心肌细胞的遗传耗竭，即使这种耗竭的程度足以引发心力衰竭的迹象。
