Article

Epicardium-derived progenitor cells require β-catenin for coronary artery formation

Development and Aging Program, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2007; 104(46):18109-14. DOI: 10.1073/pnas.0702415104
Source: PubMed

ABSTRACT We have previously identified several members of the Wnt/beta-catenin pathway that are differentially expressed in a mouse model with deficient coronary vessel formation. Systemic ablation of beta-catenin expression affects mouse development at gastrulation with failure of both mesoderm development and axis formation. To circumvent this early embryonic lethality and study the specific role of beta-catenin in coronary arteriogenesis, we have generated conditional beta-catenin-deletion mutant animals in the proepicardium by interbreeding with a Cre-expressing mouse that targets coronary progenitor cells in the proepicardium and its derivatives. Ablation of beta-catenin in the proepicardium results in lethality between embryonic day 15 and birth. Mutant mice display impaired coronary artery formation, whereas the venous system and microvasculature are normal. Analysis of proepicardial beta-catenin mutant cells in the context of an epicardial tracer mouse reveals that the formation of the proepicardium, the migration of proepicardial cells to the heart, and the formation of the primitive epicardium are unaffected. However, subsequent processes of epicardial development are dramatically impaired in epicardial-beta-catenin mutant mice, including failed expansion of the subepicardial space, blunted invasion of the myocardium, and impaired differentiation of epicardium-derived mesenchymal cells into coronary smooth muscle cells. Our data demonstrate a functional role of the epicardial beta-catenin pathway in coronary arteriogenesis.

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    • "Other studies placed Wt1 upstream of epicardial Raldh2 (a key molecule in RA metabolism ) expression (Guadix et al. 2011). RA signaling in turn has been described earlier to spearhead a signaling network that includes cross talk with Wnt and FGF signaling molecules (Fig. 3C) (Merki et al. 2005; Lavine et al. 2006; Zamora et al. 2007). Formation of the coronary vessels is tightly linked to compact zone growth and relies on overlapping signaling molecules (Olivey and Svensson 2010; Perez-Pomares and de la Pompa 2011). "
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    Cold Spring Harbor Perspectives in Medicine 10/2013; 3(10). DOI:10.1101/cshperspect.a013847 · 7.56 Impact Factor
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    • "For an epicardial progenitor to contribute as a cell source for myocardial regeneration, the epicardial cell must initially undergo an epithelial to mesenchymal transition (EMT); i.e. the epicardial cells must first lose their “epithelial-like” characteristics and migrate into the myocardium. β-catenin has been shown to be essential for normal epicardial EMT [35]. Accordingly, our results imply that ICG-001, by specifically interfering with β-catenin/CBP transcription, promotes EMT and increases the differentiation of epicardial progenitor cells, thereby contributing to the regeneration process after myocardial infarction. "
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    • "Cell Stem Cell 9, 527–540, December 2, 2011 ª2011 Elsevier Inc. 535 Gata5-CRE Lineage Tracing Suggests an Epicardial Origin for cCFU-Fs The Gata5-Cre transgenic line has been used previously to delete genes in the proepicardial/epicardial lineage (Martínez- Estrada et al., 2010; Mellgren et al., 2008; Merki et al., 2005; Zamora et al., 2007). In Gata5-Cre 3 Z/EG progeny, most large colonies (79.3% ± 5%) were GFP + /LACZ À (Figure 6C). "
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