Abstract
Unlike mammals, zebrafish can regenerate injured hearts even in the adult stage. Cardiac regeneration requires the coordination of cardiomyocyte (CM) proliferation and migration. The TGF-β/Smad3 signaling pathway has been implicated in cardiac regeneration, but the molecular mechanisms by which this pathway regulates CM proliferation and migration have not been fully illustrated. Here, we investigated the function of TGF-β/Smad3 signaling in a zebrafish model of ventricular ablation. Multiple components of this pathway were upregulated/activated after injury. Utilizing a specific inhibitor of Smad3, we detected an increased ratio of unrecovered hearts. Transcriptomic analysis suggested that the TGF-β/Smad3 signaling pathway could affect CM proliferation and migration. Further analysis demonstrated that the CM cell cycle was disrupted and the epithelial–mesenchymal transition (EMT)-like response was impaired, which limited cardiac regeneration. Altogether, our study reveals an important function of TGF-β/Smad3 signaling in CM cell cycle progression and EMT process during zebrafish ventricle regeneration.
Highlights
Myocardial infarction (MI) is a major cause of mortality worldwide (Virani et al, 2020)
The TGF-β/Smad3 signaling pathway has been reported to be vital for scar resolution in an adult zebrafish model of heart cryoinjury (Chablais and Jazwinska, 2012), and our results indicated that this pathway was activated after ventricle ablation and played important roles in ventricle regeneration
The exacerbation of different types of unrecovered hearts after SIS3 treatment and the transcriptomic analysis suggested that TGFβ/Smad3 signaling may affect CM proliferation and migration
Summary
Myocardial infarction (MI) is a major cause of mortality worldwide (Virani et al, 2020). Adult mammalian hearts cannot replenish the large number of cardiomyocytes (CMs) that are lost due to MI, and the loss of CMs eventually leads to heart failure (Porrello et al, 2011). Cell migration is necessary for cardiac regeneration (Itou et al, 2012), and ventricular and atrial CMs can migrate into and replenish injured areas (Kikuchi et al, 2010; Zhang et al, 2013). Epicardial cells can enter the myocardial layer through the process of epithelial–mesenchymal transition (EMT), during which the expression of EMT marker genes, such as snail, twist, and vimentin, are upregulated (Lepilina et al, 2006; Kim et al, 2010). The regulation of cell migration and how it coordinates with other cellular processes, such as cell proliferation, during cardiac regeneration remain largely unknown
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