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.

Download full-text

Full-text

Available from: Pilar ruiz-lozano, Mar 20, 2015
0 Followers
 · 
145 Views
  • Source
    [Show abstract] [Hide abstract]
    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 · 7.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 22.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An epithelial sheet, the epicardium, lines the surface of the heart. In the developing embryo, the epicardium expresses the transcriptional regulator Wilm's Tumor Gene 1 (Wt1). Through incompletely understood mechanisms, Wt1 inactivation derails normal heart development. We investigated mechanisms by which Wt1 regulates heart development and epicardial epithelial to mesenchymal transition (EMT). We used genetic lineage tracing approaches to track and isolate epicardium and epicardium derivatives in hearts lacking Wt1 (Wt1(KO)). Wt1(KO) hearts had diminished proliferation of compact myocardium and impaired coronary plexus formation. Wt1(KO) epicardium failed to undergo EMT. Wt1(KO) epicardium expressed reduced Lef1 and Ctnnb1 (β-catenin), key components of the canonical Wnt/β-catenin signaling pathway. Wt1(KO) epicardium expressed decreased levels of canonical Wnt downstream targets Axin2, Cyclin D1, and Cyclin D2 and exhibited decreased activity of the Batgal Wnt/β-catenin reporter transgene, suggestive of diminished canonical Wnt signaling. Hearts with epicardium-restricted Ctnnb1 loss of function resembled Wt1(KO) hearts and also failed to undergo epicardial EMT. However, Ctnnb1 inactivation did not alter WT1 expression, positioning Wt1 upstream of canonical Wnt/β-catenin signaling. Wnt5a, a prototypic non-canonical Wnt with enriched epicardial expression, and Raldh2, a key regulator of retinoic acid signaling confined to the epicardium, were also markedly downregulated in Wt1(KO) epicardium. Hearts lacking Wnt5a or Raldh2 shared phenotypic features with Wt1(KO). Although Wt1 has been proposed to regulate EMT by repressing E-cadherin, we detected no change in E-cadherin in Wt1(KO) epicardium. Collectively, our study shows that Wt1 regulates epicardial EMT and heart development through canonical Wnt, non-canonical Wnt, and retinoic acid signaling pathways.
    Developmental Biology 05/2011; 356(2):421-31. DOI:10.1016/j.ydbio.2011.05.668 · 3.64 Impact Factor