Wnt/β-catenin signaling in heart regeneration

Abstract

The ability to repair damaged or lost tissues varies significantly among vertebrates. The regenerative ability of the heart is clinically very relevant, because adult teleost fish and amphibians can regenerate heart tissue, but we mammals cannot. Interestingly, heart regeneration is possible in neonatal mice, but this ability is lost within 7 days after birth. In zebrafish and neonatal mice, lost cardiomyocytes are regenerated via proliferation of spared, differentiated cardiomyocytes. While some cardiomyocyte turnover occurs in adult mammals, the cardiomyocyte production rate is too low in response to injury to regenerate the heart. Instead, mammalian hearts respond to injury by remodeling of spared tissue, which includes cardiomyocyte hypertrophy. Wnt/β-catenin signaling plays important roles during vertebrate heart development, and it is re-activated in response to cardiac injury. In this review, we discuss the known functions of this signaling pathway in injured hearts, its involvement in cardiac fibrosis and hypertrophy, and potential therapeutic approaches that might promote cardiac repair after injury by modifying Wnt/β-catenin signaling. Regulation of cardiac remodeling by this signaling pathway appears to vary depending on the injury model and the exact stages that have been studied. Thus, conflicting data have been published regarding a potential role of Wnt/β-catenin pathway in promotion of fibrosis and cardiomyocyte hypertrophy. In addition, the Wnt inhibitory secreted Frizzled-related proteins (sFrps) appear to have Wnt-dependent and Wnt-independent roles in the injured heart. Thus, while the exact functions of Wnt/β-catenin pathway activity in response to injury still need to be elucidated in the non-regenerating mammalian heart, but also in regenerating lower vertebrates, manipulation of the pathway is essential for creation of therapeutically useful cardiomyocytes from stem cells in culture. Hopefully, a detailed understanding of the in vivo role of Wnt/β-catenin signaling in injured mammalian and non-mammalian hearts will also contribute to the success of current efforts towards developing regenerative therapies.

Keywords: Beta-catenin; Cardiomyocyte; Fibrosis; Heart; Hypertrophy; Regeneration; Wnt; Zebrafish; sFrp.

Fig. 1

The Wnt/β-catenin signaling pathway. In the Wnt-off state, defined by the absence of an active Wnt ligand, β-catenin is phosphorylated by the destruction complex (formed from the two kinases Gsk3 and Ck1, the scaffolding protein Axin, and the tumor suppressor Apc) and degraded by the ubiquitin-proteasome pathway. In the Wnt-on state, active Wnt ligands interact with the Fz receptors and the Lrp5/6 coreceptor. Phosphorylation of Lrp5/6 by Gsk3 and Ck1 recruits Dvl and Axin to the receptor complex and hence inhibits the destruction complex. This, in turn, inhibits β-catenin phosphorylation and stabilizes β-catenin in the cytoplasm. β-catenin is then translocated into the nucleus, by a complex including Fam53b/Smp, and regulates target gene expression with the Tcf/Lef transcription factors. Many modulators including the inhibitors sFrps and Wif are known to tightly regulate the signaling cascade

Fig. 2

Roles of Wnt/β-catenin signaling during vertebrate heart development. Wnt/β-catenin signaling is required for heart development in a biphasic manner: while the activation of the pathway promotes mesoderm specification in early phases of hESC differentiation, it hampers CM differentiation at later stages. This late-stage suppression can act through the cardiac differentiation inducer Mesp1, which activates the Wnt inhibitor Dkk1. Wnt/β-catenin signaling can also regulate CM proliferation through Gsk3 by regulating β-catenin activity

Fig. 3

Wnt-dependent and Wnt-independent roles of secreted Frizzled-related proteins (sFrps). sFrp-2 can block hypoxia-induced CM apoptosis by activating a Wnt/β-catenin pathway. On the other hand, sFrp-2 can induce collagen deposition and fibrosis via enhancing Bmp1 function, which occurs through a Wnt-independent pathway