The Small Molecule Wnt Signaling Modulator ICG-001 Improves Contractile Function in Chronically Infarcted Rat Myocardium

Sasaki, Taro; Hwang, Hyeon-Shik; Nguyen, Carvell T.; Kloner, Robert A.; Kahn, Michaël

doi:10.1371/journal.pone.0075010

Cited by 76 publications

(71 citation statements)

References 63 publications

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“…This paradigm appears to be generalizable to both epithelial and non-epithelial adult somatic stem/progenitor cells. In support of the universality of this model, similar ␤-catenin/co-activator interactions have been shown to regulate differentiation of other stem/progenitor cells including mouse and human embryonic stem cells (9,34), cardiovascular progenitors (35,36), neuronal progenitors (37), hepatoblasts and hepatic tumor initiating cells (38), and leukemia cells (39). This report extends these studies to elucidate a novel intersection between non-canonical and canonical signaling arms, further highlighting the complexity of Wnt signaling.…”

Section: Wnt5a/pkc/␤-catenin In Progenitor Cell Differentiationsupporting

confidence: 69%

p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)

Rieger

Zhou

Solomon

et al. 2016

Journal of Biological Chemistry

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Maintenance of stem/progenitor cell-progeny relationships is required for tissue homeostasis during normal turnover and repair. Wnt signaling is implicated in both maintenance and differentiation of adult stem/progenitor cells, yet how this pathway serves these dichotomous roles remains enigmatic. We previously proposed a model suggesting that specific interaction of ␤-catenin with either of the homologous Kat3 co-activators, p300 or CREB-binding protein, differentially regulates maintenance versus differentiation of embryonic stem cells. Limited knowledge of endogenous mechanisms driving differential ␤-catenin/co-activator interactions and their role in adult somatic stem/progenitor cell maintenance versus differentiation led us to explore this process in defined models of adult progenitor cell differentiation. We focused primarily on alveolar epithelial type II (AT2) cells, progenitors of distal lung epithelium, and identified a novel axis whereby WNT5a/protein kinase C (PKC) signaling regulates specific ␤-catenin/co-activator interactions to promote adult progenitor cell differentiation. p300/␤-catenin but not CBP/␤-catenin interaction increases as AT2 cells differentiate to a type I (AT1) cell-like phenotype. Additionally, p300 transcriptionally activates AT1 cell-specific gene Aqp-5. IQ-1, a specific inhibitor of p300/␤-catenin interaction, prevents differentiation of not only primary AT2 cells, but also tracheal epithelial cells, and C2C12 myoblasts. p300 phosphorylation at Ser-89 enhances p300/␤-catenin interaction, concurrent with alveolar epithelial cell differentiation. WNT5a, a traditionally non-canonical WNT ligand regulates Ser-89 phosphorylation and p300/␤-catenin interactions in a PKC-dependent manner, likely involving PKC. These studies identify a novel intersection of canonical and non-canonical Wnt signaling in adult progenitor cell differentiation that has important implications for targeting ␤-catenin to modulate adult progenitor cell behavior in disease.

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Section: Wnt5a/pkc/␤-catenin In Progenitor Cell Differentiationsupporting

confidence: 69%

p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)

Rieger

Zhou

Solomon

et al. 2016

Journal of Biological Chemistry

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“…Our in vivo chemical screen using WNT-974 has identified a tissue that is not detrimentally affected by suppression of Wnt signaling and that may benefit from diminished fibrotic responses induced by Porcn inhibition. Indeed, other classes of small molecules with inhibitory activity for Wnt signaling have similarly shown beneficial responses in heart tissue; albeit, these molecules have not progressed further in clinical development for managing heart disease (42,43). We also reason that other tissues, like the heart (Fig.…”

Section: Discussionmentioning

confidence: 98%

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Moon

Zhou

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, COL6A1, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.

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“…In contrast to embryonic development, in differentiated SMCs, activation of WNT induced cell proliferation, whereas its inhibition improved muscle contractility: a significant induction of WNT2 and WNT4 mRNA was detected in proliferating vascular SMCs (50), and inhibition of WNT signaling improved contractile function in experimental models of myocardial infarction (51). Our data support the latter finding: we show that WNT2 inhibition by miR-199a-5p occurred simultaneously with activation of both myocardin-and MRTF-A-dependent SM differentiation programs in SMCs overexpressing miR-199a-5p.…”

Section: Journal Of Biological Chemistry 7081mentioning

confidence: 93%

MicroRNA MiR-199a-5p Regulates Smooth Muscle Cell Proliferation and Morphology by Targeting WNT2 Signaling Pathway

Gheinani

Burkhard

Rehrauer³

et al. 2015

Journal of Biological Chemistry

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Background: MicroRNA miR-199a-5p, implicated in cell motility and proliferation, is highly expressed in bladder smooth muscle. Results: MiR-199a-5p regulates WNT, cytoskeleton, and cell cycle pathways in urothelial and smooth muscle cells and promotes myocardin-driven gene expression. Conclusion: MiR-199a-5p acts via its target WNT2 to control smooth muscle proliferation and morphology. Significance: MiR-199a-5p is a key modulator of smooth muscle hypertrophy, relevant for bladder organ remodeling.

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The Small Molecule Wnt Signaling Modulator ICG-001 Improves Contractile Function in Chronically Infarcted Rat Myocardium

Cited by 76 publications

References 63 publications

p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)

p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC)

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

MicroRNA MiR-199a-5p Regulates Smooth Muscle Cell Proliferation and Morphology by Targeting WNT2 Signaling Pathway

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