Epicardium-derived progenitor cells require -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: 9.67). 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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    ABSTRACT: The mammalian heart is a highly specialized organ, comprised of many different cell types arising from distinct embryonic progenitor populations during cardiogenesis. Three precursor populations have been identified to contribute to different myocytic and nonmyocytic cell lineages of the heart: cardiogenic mesoderm cells (CMC), the proepicardium (PE), and cardiac neural crest cells (CNCCs). This review will focus on molecular cues necessary for proper induction, expansion, and lineage-specific differentiation of these progenitor populations during cardiac development in vivo. Moreover, we will briefly discuss how the knowledge gained on embryonic heart progenitor biology can be used to develop novel therapeutic strategies for the management of congenital heart disease as well as for improvement of cardiac function in ischemic heart disease.
    Cold Spring Harbor Perspectives in Medicine 10/2013; 3(10). DOI:10.1101/cshperspect.a013847 · 9.47 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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    ABSTRACT: The adult mammalian heart has limited capability for self-repair after myocardial infarction. Therefore, therapeutic strategies that improve post-infarct cardiac function are critically needed. The small molecule ICG-001 modulates Wnt signaling and increased the expression of genes beneficial for cardiac regeneration in epicardial cells. Lineage tracing experiments, demonstrated the importance of β-catenin/p300 mediated transcription for epicardial progenitor contribution to the myocardium. Female rats given ICG-001 for 10 days post-occlusion significantly improved ejection fraction by 8.4%, compared to controls (P<0.05). Taken together, Wnt modulation via β-catenin/CBP inhibition offers a promising therapeutic strategy towards restoration of myocardial tissues and an enhancement of cardiac functions following infarction.
    PLoS ONE 09/2013; 8(9):e75010. DOI:10.1371/journal.pone.0075010 · 3.23 Impact Factor
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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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    ABSTRACT: Colony-forming units - fibroblast (CFU-Fs), analogous to those giving rise to bone marrow (BM) mesenchymal stem cells (MSCs), are present in many organs, although the relationship between BM and organ-specific CFU-Fs in homeostasis and tissue repair is unknown. Here we describe a population of adult cardiac-resident CFU-Fs (cCFU-Fs) that occupy a perivascular, adventitial niche and show broad trans-germ layer potency in vitro and in vivo. CRE lineage tracing and embryo analysis demonstrated a proepicardial origin for cCFU-Fs. Furthermore, in BM transplantation chimeras, we found no interchange between BM and cCFU-Fs after aging, myocardial infarction, or BM stem cell mobilization. BM and cardiac and aortic CFU-Fs had distinct CRE lineage signatures, indicating that they arise from different progenitor beds during development. These diverse origins for CFU-Fs suggest an underlying basis for differentiation biases seen in different CFU-F populations, and could also influence their capacity for participating in tissue repair.
    Cell stem cell 12/2011; 9(6):527-40. DOI:10.1016/j.stem.2011.10.002 · 22.27 Impact Factor
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