Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes.
Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes.
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最近的研究表明，哺乳动物，包括人类，在整个出生后的生活中保持一定的更新心肌细胞的能力。然而，在急性心肌梗死（MI）等损伤后，几乎没有或没有显著的心肌再生。相比之下，斑马鱼可以有效地再生失去的心肌，为理解自然心脏再生如何被阻断或增强提供了一个模型。在没有适用于成年斑马鱼的谱系追踪技术的情况下，新再生心肌的细胞起源仍然不清楚。在这里，我们使用新的遗传命运绘图方法来识别心室尖切除后被激活并对心肌再生做出显着贡献的心肌细胞群。通过使用转基因报告菌株，我们发现在创伤后一周内，在表达定位于损伤部位周围和内部的增殖心肌细胞之前，整个心外膜下心室层的心肌细胞触发胚胎心脏发生基因gata4的表达。对明显再生前表达gata4的细胞或损伤前表达收缩基因cmlc2的细胞进行基于Cre重组酶的谱系追踪，每种细胞都标记了随后再生的大部分心肌。通过对整个心室表面心肌的光学电压标测，我们发现在损伤后2至4周，现有和再生心肌细胞之间重新建立了电传导。在损伤和延长FGF受体抑制以阻止心脏再生并使瘢痕形成后，信号传导阻滞的实验释放导致损伤的心室壁的gata4表达和形态学改善，而没有瘢痕组织的损失。我们的研究结果表明，电偶联心肌再生切除损伤后，主要是通过激活和扩张的心肌细胞群，研究结果与促进受伤的人类心脏再生的影响。
Recent studies indicate that mammals, including humans, maintain some capacity to renew cardiomyocytes throughout postnatal life. Yet, there is little or no significant cardiac muscle regeneration after an injury like acute myocardial infarction (MI). By contrast, zebrafish efficiently regenerate lost cardiac muscle, providing a model for understanding how natural heart regeneration may be blocked or enhanced. In the absence of lineage-tracing technology applicable to adult zebrafish, the cellular origins of newly regenerated cardiac muscle have remained unclear. Here, we used new genetic fate-mapping approaches to identify a population of cardiomyocytes that become activated after resection of the ventricular apex and contribute prominently to cardiac muscle regeneration. Through use of a transgenic reporter strain, we found that cardiomyocytes throughout the subepicardial ventricular layer trigger expression of the embryonic cardiogenesis gene gata4 within a week of trauma, before expression localizes to proliferating cardiomyocytes surrounding and within the injury site. Cre recombinase-based lineage-tracing of cells expressing gata4 before evident regeneration, or of cells expressing the contractile gene cmlc2 before injury, each labeled a majority of cardiac muscle in the ensuing regenerate. By optical voltage mapping of surface myocardium in whole ventricles, we found that electrical conduction is re-established between existing and regenerated cardiomyocytes between 2 and 4 weeks post-injury. After injury and prolonged Fgf receptor inhibition to arrest cardiac regeneration and enable scar formation, experimental release of the signaling block led to gata4 expression and morphological improvement of the injured ventricular wall without loss of scar tissue. Our results indicate that electrically coupled cardiac muscle regenerates after resection injury primarily through activation and expansion of cardiomyocyte populations, findings with implications for promoting regeneration of the injured human heart.
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影响因子：
64.5
作者：
Bersell, Kevin;Arab, Shima;Kuehn, Bernhard
通讯作者：
Kuehn, Bernhard
影响因子：
56.9
作者：
Poss, KD;Wilson, LG;Keating, MT
通讯作者：
Keating, MT
影响因子：
14.9
作者：
Indra, AK;Warot, X;Metzger, D
通讯作者：
Metzger, D
DOI：
10.1073/pnas.1834204100
发表时间：
2003-09-30
影响因子：
11.1
作者：
Raya, A;Koth, CM;Izpisúa-Belmonte, JC
通讯作者：
Izpisúa-Belmonte, JC
影响因子：
64.8
作者：
Laugwitz, KL;Moretti, A;Chien, KR
通讯作者：
Chien, KR