Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature. 2010 Mar 25;464(7288):601-5. doi: 10.1038/nature08804.
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 such as acute myocardial infarction. 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. Using new genetic fate-mapping approaches, here we identify a population of cardiomyocytes that become activated after resection of the ventricular apex and contribute prominently to cardiac muscle regeneration. Through the 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 labelled most 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 fibroblast growth factor receptor inhibition to arrest cardiac regeneration and enable scar formation, experimental release of the signalling 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. These findings have implications for promoting regeneration of the injured human heart.
最近的研究表明,哺乳动物(包括人类)在出生后仍能维持一定的心肌细胞再生能力。然而,在急性心肌梗死等损伤后,心肌几乎没有或没有明显的再生。相比之下,斑马鱼能够有效地再生失去的心肌,为了解自然心脏再生如何可能被阻断或增强提供了一个模型。在缺乏适用于成年斑马鱼的谱系追踪技术的情况下,新再生心肌的细胞来源仍不清楚。在这里,我们使用新的遗传谱系追踪方法,鉴定出一群在心室顶部切除后被激活的心肌细胞,这些细胞对心肌再生有重要贡献。通过使用转基因报告品系,我们发现,在心包膜下心室层的整个区域,心肌细胞在创伤后一周内触发胚胎心脏发生基因 gata4 的表达,然后表达定位在损伤部位周围和内部的增殖性心肌细胞。在明显再生之前表达 gata4 的细胞或在损伤之前表达收缩基因 cmlc2 的细胞的 Cre 重组酶系追踪,每个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进行光学电压映射,我们发现,在损伤后 2 至 4 周,在现有和再生的心肌细胞之间重新建立了电传导。在损伤后和长时间抑制成纤维细胞生长因子受体以阻止心脏再生和形成疤痕后,信号阻断的实验释放导致 gata4 的表达和损伤心室壁的形态改善,而不会损失疤痕组织。我们的研究结果表明,切除损伤后,电耦联的心肌可以再生,主要是通过激活和扩大心肌细胞群体。这些发现对促进人类受损心脏的再生具有重要意义。
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