The regenerative capacity of the zebrafish heart is dependent on TGFβ signaling

Abstract

SUMMARYMammals respond to a myocardial infarction by irreversible scar formation. By contrast, zebrafish are able to resolve the scar and to regenerate functional cardiac muscle. It is not known how opposing cellular responses of fibrosis and new myocardium formation are spatially and temporally coordinated during heart regeneration in zebrafish. Here, we report that the balance between the reparative and regenerative processes is achieved through Smad3-dependent TGF signaling. The type I receptor alk5b (tgfbr1b) is expressed in both fibrotic and cardiac cells of the injured heart. TGF ligands are locally induced following cryoinjury and activate the signaling pathway both in the infarct area and in cardiomyocytes in the vicinity of the trauma zone. Inhibition of the relevant type I receptors with the specific chemical inhibitor SB431542 qualitatively altered the infarct tissue and completely abolished heart regeneration. We show that transient scar formation is an essential step to maintain robustness of the damaged ventricular wall prior to cardiomyocyte replacement. Taking advantage of the reversible action of the inhibitor, we dissected the multifunctional role of TGF signaling into three crucial processes: collagen-rich scar deposition, Tenascin Cassociated tissue remodeling at the infarct-myocardium interface, and cardiomyocyte proliferation. Thus, TGF signaling orchestrates the beneficial interplay between scar-based repair and cardiomyocyte-based regeneration to achieve complete heart regeneration.

Hydrogen peroxide primes heart regeneration with a derepression mechanism

“…In spite of great efforts, the molecular mechanisms underlying heart regeneration remain incompletely understood. Previous reports support that developmental signaling pathways such as FGF, PDGF, retinoid acid, TGFβ and integrin are essential for adult zebrafish heart regeneration [19][20][21][22][23]. Ventricular resection induces expression of fgfr2/4 in the epicardium and their ligand fgf17b in the myocardium, and conditional blocking of the FGF signaling by overexpression of dominant-negative FGFR1 substantially increases fibrin/ collagen deposits and diminishes myocardial regeneration, supporting a notion that the FGF signaling promotes myocardial regeneration through epicardial-myocardial interaction [21].…”

Activation of Smad2 but not Smad3 is required to mediate TGF-β signaling during axolotl limb regeneration

“…p-Smad3 has also been described in zebrafish heart regeneration. Activation of Smad3 via Activin/TGF-β in zebrafish heart leads to the formation of a transient scar that is later resolved to achieve regeneration (Chablais and Jazwinska, 2012). Treatment with SB-431542 prevents phosphorylation of Smad3 and hence the heart regeneration process in zebrafish is inhibited.…”

Notch signalling restricts inflammation and serpine1 expression in the dynamic endocardium of the regenerating zebrafish heart

“…This raises the hypothesis that endocardial signals may regulate regenerative processes, and that endocardial maturation might be crucial for cardiac regeneration to progress from the inflammatory to the reparative phase (Chablais and Jazwinska, 2012a). During inflammation, vascular endothelial cells mediate the recruitment, adherence and passage of inflammatory cells (Pober and Sessa, 2007).…”