Wnt Signaling in Regulation of Stem Cells

Paik, David T.; Hatzopoulos, Antonis K.

doi:10.1002/9781118695746.ch1

Cited by 2 publications

(3 citation statements)

References 92 publications

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“…This problem is particularly acute in the Wnt signaling pathway, which consists of 19 ligands and 10 frizzled receptors with overlapping, often redundant expression and function. 57,58 However, it is noteworthy that the observed phenotypes are distinct from those described in αMHC- Wnt11 transgenic mice, which displayed cardiomyopathy due to hypertrophic ventricular myocytes, 59 suggesting that, at least part of the results are specific to the Wnt10b ligand. Thus, development of Wnt10b administration protocols, or compounds designed to mimic Wnt10b, will likely help orchestrate stable blood vessel formation after injury, improve cardiac tissue recovery, and potentially decrease ventricular remodeling and heart failure.…”

Section: Discussionmentioning

confidence: 95%

Wnt10b Gain-of-Function Improves Cardiac Repair by Arteriole Formation and Attenuation of Fibrosis

Paik

Rai

Ryzhov

et al. 2015

Circulation Research

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Rationale Myocardial infarction causes irreversible tissue damage, leading to heart failure (HF). We recently discovered that canonical Wnt signaling and the Wnt10b ligand are strongly induced in mouse hearts after infarction. Wnt10b regulates cell fate in various organs, but its role in the heart is unknown. Objective To investigate the effect of Wnt10b gain-of-function on cardiac repair mechanisms and assess its potential to improve ventricular function after injury. Methods and Results Histological and molecular analyses showed that Wnt10b is expressed in cardiomyocytes and localized in the intercalated discs of mouse and human hearts. After coronary artery ligation or cryoinjury in mice, Wnt10b is strongly and transiently induced in peri-infarct area cardiomyocytes during granulation tissue formation. To determine the effect of Wnt10b on neovascularization and fibrosis, we generated a mouse line to increase endogenous Wnt10b levels in cardiomyocytes. We found that gain of Wnt10b function orchestrated a recovery phenotype characterized by robust neovascularization of the injury zone, less myofibroblasts, reduced scar size, and improved ventricular function compared to wild-type mice. Wnt10b stimulated expression of Vascular Endothelial Growth Factor Receptor 2 (Vegfr-2) in endothelial cells and Angiopoietin-1 in vascular smooth muscle cells through NF-κB activation. These effects coordinated endothelial growth and smooth muscle cell recruitment, promoting robust formation of large, coronary-like blood vessels. Conclusion Wnt10b gain-of-function coordinates arterial formation and attenuates fibrosis in cardiac tissue after injury. Because generation of mature blood vessels is necessary for efficient perfusion, our findings could lead to novel strategies to optimize the inherent repair capacity of the heart and prevent the onset of HF.

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Section: Discussionmentioning

confidence: 95%

Wnt10b Gain-of-Function Improves Cardiac Repair by Arteriole Formation and Attenuation of Fibrosis

Paik

Rai

Ryzhov

et al. 2015

Circulation Research

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“…Wnt/β-catenin is a highly conserved signaling pathway , that is important for development. Aberrant Wnt signaling is involved in many diseases, such as cancer (in which the pathway is inappropriately activated) and Alzheimer’s disease and osteoporosis (in which the pathway is attenuated). − In recent years, Wnt antagonists have attracted attention due to the potential applications in the clinical treatment of cancer. − Appropriate activation of Wnt signaling pathways could also be useful in other clinical applications, such as hematopoietic stem cell (HSC) expansion and the treatment of osteoporosis …”

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confidence: 99%

“…6−9 Appropriate activation of Wnt signaling pathways could also be useful in other clinical applications, such as hematopoietic stem cell (HSC) expansion and the treatment of osteoporosis. 10 Lycorine is a naturally occurring multifunctional benzylphenethylamine alkaloid (Figure 1a) of considerable interest. 11−14 Previous studies have identified that lycorine derivatives are novel HCV (hepatitis C virus) inhibitors that act via novel mechanisms.…”

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confidence: 99%

Design, Synthesis, and Structural Optimization of Lycorine-Derived Phenanthridine Derivatives as Wnt/β-Catenin Signaling Pathway Agonists

et al. 2015

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Lycorine is a benzylphenethylamine-type alkaloid member of the Amaryllidaceae family. A lycorine derivative, HLY78, was previously identified as a new Wnt/β-catenin signaling pathway agonist that targets the DAX domain of axin. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships of lycorine-derived phenanthridine derivatives as agonists of the Wnt/β-catenin signaling pathway are presented. This research suggests that triazole groups are important pharmacophores for Wnt activation; triazole groups at C-8 and C-9 of phenanthridine compounds markedly enhanced Wnt activation. A C-11-C-12 single bond is also important for Wnt activation. On the basis of these findings, two Wnt agonists were designed and synthesized. The results for these agonists indicated that the combination of a 4-ethyldihydrophenanthridine skeleton and a triazole substituent improves Wnt activation. These compounds may be useful in further pharmacological or biological studies.

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Wnt Signaling in Regulation of Stem Cells

Cited by 2 publications

References 92 publications

Wnt10b Gain-of-Function Improves Cardiac Repair by Arteriole Formation and Attenuation of Fibrosis

Wnt10b Gain-of-Function Improves Cardiac Repair by Arteriole Formation and Attenuation of Fibrosis

Design, Synthesis, and Structural Optimization of Lycorine-Derived Phenanthridine Derivatives as Wnt/β-Catenin Signaling Pathway Agonists

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