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Wnt/β-catenin signaling in heart regeneration.

Ozhan G, Weidinger G - Cell Regen (Lond) (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Izmir Biomedicine and Genome Center (iBG-izmir), Dokuz Eylul University, Inciralti-Balcova, 35340 Izmir, Turkey ; Department of Medical Biology and Genetics, Dokuz Eylul University Medical School, Inciralti-Balcova, 35340 Izmir, Turkey.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig1: 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

Mentions: Wnt/β-catenin signaling has vital functions during embryonic development, adult homeostasis, and tissue and organ regeneration [47, 48]. The pathway takes its name from a family of secreted glycoproteins, the Wnt proteins, which act as pathway ligands and from the downstream effector molecule, β-catenin [49, 50]. In the absence of an active Wnt ligand, i.e., in the Wnt-off state, β-catenin is phosphorylated by a cytoplasmic complex of proteins (the “destruction complex”) that includes two serine/threonine kinases, namely Glycogen synthase kinase 3β (Gsk3β) and Casein kinase 1 (Ck1); the scaffolding protein Axin; and the tumor suppressor Adenomatous polyposis coli (Apc) (Fig. 1) [51, 52]. Phosphorylated β-catenin is ubiquitinated and targeted for degradation by the proteasome pathway [47, 50, 53, 54]. If active Wnt ligands are available, i.e., in the Wnt-on state, they interact with Frizzled (Fz) receptors and the coreceptor Low-density lipoprotein receptor-related proteins 5/6 (Lrp5/6) [51, 55]. Lrp5/6 is then phosphorylated at its intracellular domain by Gsk3β and Ck1 in raft plasma membrane domains and internalized into intracellular vesicles [47, 56–58]. Lrp5/6 phosphorylation recruits the cytoplasmic scaffolding proteins Dishevelled (Dvl) and Axin to the receptor complex, leading to inhibition of the destruction complex and hence inhibition of β-catenin phosphorylation (Fig. 1) [51, 59]. This results in β-catenin stabilization in the cytoplasm and its translocation into the nucleus, which is in part mediated by Fam53b/Smp [60]. β-catenin regulates target gene expression with the transcription factors of the T cell factor (Tcf)/Lymphoid enhancer factor (Lef) family [47, 51, 61, 62]. The Wnt-off-state can also be brought about by a plethora of pathway inhibitors [63, 64], some of which act by binding to the Wnt ligands, such as secreted Frizzled-related proteins (sFrps) and Wnt inhibitory factor (Wif) [65].Fig. 1


Wnt/β-catenin signaling in heart regeneration.

Ozhan G, Weidinger G - Cell Regen (Lond) (2015)

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
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4495933&req=5

Fig1: 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
Mentions: Wnt/β-catenin signaling has vital functions during embryonic development, adult homeostasis, and tissue and organ regeneration [47, 48]. The pathway takes its name from a family of secreted glycoproteins, the Wnt proteins, which act as pathway ligands and from the downstream effector molecule, β-catenin [49, 50]. In the absence of an active Wnt ligand, i.e., in the Wnt-off state, β-catenin is phosphorylated by a cytoplasmic complex of proteins (the “destruction complex”) that includes two serine/threonine kinases, namely Glycogen synthase kinase 3β (Gsk3β) and Casein kinase 1 (Ck1); the scaffolding protein Axin; and the tumor suppressor Adenomatous polyposis coli (Apc) (Fig. 1) [51, 52]. Phosphorylated β-catenin is ubiquitinated and targeted for degradation by the proteasome pathway [47, 50, 53, 54]. If active Wnt ligands are available, i.e., in the Wnt-on state, they interact with Frizzled (Fz) receptors and the coreceptor Low-density lipoprotein receptor-related proteins 5/6 (Lrp5/6) [51, 55]. Lrp5/6 is then phosphorylated at its intracellular domain by Gsk3β and Ck1 in raft plasma membrane domains and internalized into intracellular vesicles [47, 56–58]. Lrp5/6 phosphorylation recruits the cytoplasmic scaffolding proteins Dishevelled (Dvl) and Axin to the receptor complex, leading to inhibition of the destruction complex and hence inhibition of β-catenin phosphorylation (Fig. 1) [51, 59]. This results in β-catenin stabilization in the cytoplasm and its translocation into the nucleus, which is in part mediated by Fam53b/Smp [60]. β-catenin regulates target gene expression with the transcription factors of the T cell factor (Tcf)/Lymphoid enhancer factor (Lef) family [47, 51, 61, 62]. The Wnt-off-state can also be brought about by a plethora of pathway inhibitors [63, 64], some of which act by binding to the Wnt ligands, such as secreted Frizzled-related proteins (sFrps) and Wnt inhibitory factor (Wif) [65].Fig. 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Izmir Biomedicine and Genome Center (iBG-izmir), Dokuz Eylul University, Inciralti-Balcova, 35340 Izmir, Turkey ; Department of Medical Biology and Genetics, Dokuz Eylul University Medical School, Inciralti-Balcova, 35340 Izmir, Turkey.

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.

No MeSH data available.


Related in: MedlinePlus