Epicardium-derived progenitor cells require beta-catenin for coronary artery formation (original) (raw)
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Nature Genetics, 2010
Here we show that an epicardial-specific knockout of the gene encoding Wilms' tumor-1 (Wt1) leads to a reduction in mesenchymal progenitor cells and their derivatives. We show that Wt1 is essential for repression of the epithelial phenotype in epicardial cells and during embryonic stem cell differentiation through direct transcriptional regulation of the genes encoding Snail (Snai1) and E-cadherin (Cdh1), two of the major mediators of EMT. Some mesodermal lineages do not form in Wt1-null embryoid bodies, but this effect is rescued by the expression of Snai1, underscoring the importance of EMT in generating these differentiated cells. These new insights into the molecular mechanisms regulating cardiovascular progenitor cells and EMT will shed light on the pathogenesis of heart diseases and may help the development of cell-based therapies.
Journal of Cell Biology, 2004
uring heart development endocardial cells within the atrio-ventricular (AV) region undergo TGF dependent epithelial-mesenchymal transformation (EMT) and invade the underlying cardiac jelly. This process gives rise to the endocardial cushions from which AV valves and part of the septum originate. In this paper we show that in mouse embryos and in AV explants TGF  induction of endocardial EMT is strongly inhibited in mice deficient for endothelial -catenin, leading to a lack of heart cushion formation. Using a Wnt-signaling reporter mouse strain, we demonstrated in vivo and ex vivo that D EMT in heart cushion is accompanied by activation of -catenin/TCF/Lef transcriptional activity. In cultured endothelial cells, TGF  2 induces ␣-smooth muscle actin (␣ SMA) expression. This process was strongly reduced in -catenin null cells, although TGF  2 induced smad phosphorylation was unchanged. These data demonstrate an involvement of -catenin/TCF/Lef transcriptional activity in heart cushion formation, and suggest an interaction between TGF  and Wnt-signaling pathways in the induction of endothelialmesenchymal transformation.
Cytology and Genetics, 2014
Wnt/β catenin signaling has a great and diverse influence on the formation, development, and vital activity of a great number of vertebrate tissues, including heart tissue. The role of Wnt/β catenin signal ing and β catenin itself in the processes of cardiogenesis and adult myocardium functioning is not fully elu cidated to date. The current review regards the attempt to generalize contemporary literature data on partic ipation of this signaling pathway in embryogenesis and postnatal heart development, as well as in adult myo cardium functioning in normal conditions and during stress adaptation, and aging, resulting in hypertrophy and heart remodeling. Based on the experimental articles and reviews, we can assume that Wnt/β catenin sig naling pathway is involved not only in controlling the cardiogenesis but also in processes of adaptation and remodeling of the adult organ. This control can be characterized as complicated and multistep and β catenin appears to be a prospective candidate as a target for development of new approaches to adult myocardium pathologies therapy.
Journal of Cell Science, 2015
During vertebrate development, mesodermal fate choices are regulated by interactions between morphogens such as activin/nodal, BMPs and Wnt/β-catenin that define anterior-posterior patterning and specify downstream derivatives including cardiomyocyte, endothelial and hematopoietic cells. We used human embryonic stem cells to explore how these pathways control mesodermal fate choices in vitro. Varying doses of activin A and BMP4 to mimic cytokine gradient polarization in the anterior-posterior axis of the embryo led to differential activity of Wnt/β-catenin signaling and specified distinct anterior-like (high activin/ low BMP) and posterior-like (low activin/high BMP) mesodermal populations. Cardiogenic mesoderm was generated under conditions specifying anterior-like mesoderm, whereas blood-forming endothelium was generated from posterior-like mesoderm, and vessel-forming CD31 + endothelial cells were generated from all mesoderm origins. Surprisingly, inhibition of β-catenin signaling led to the highly efficient respecification of anterior-like endothelium into beating cardiomyocytes. Cardiac respecification was not observed in posterior-derived endothelial cells. Thus, activin/BMP gradients specify distinct mesodermal subpopulations that generate cell derivatives with unique angiogenic, hemogenic and cardiogenic properties that should be useful for understanding embryogenesis and developing therapeutics.
In Vitro Cellular & Developmental Biology - Animal, 2017
Cardiomyocyte (CM) differentiation from proepicardial organ-(PEO) and embryonic epicardium (eEpi)-derived cells or EPDCs in a developing heart emerges as a wide interest in purview of cardiac repair and regenerative medicine. eEpi originates from the precursor PEO and EPDCs, which contribute to several cardiac cell types including smooth muscle cells, fibroblasts, endothelial cells, and CMs during cardiogenesis. Here in this report, we have analyzed several cardiac lineage-specific marker gene expressions between PEO and eEpi cells. We have found that PEO-derived cells show increased level of CM lineagespecific marker gene expression compared to eEpi cells. Moreover, Wnt signaling activation results in increased level of CM-specific marker gene expression in both PEO and eEpi cells in culture. Interestingly, Wnt signaling activation also increases the number of proliferating and sarcomeric myosin (Mf20)-positive cells in eEpi explant culture. Together, this data suggests that eEpi cells as a source for CM differentiation and Wnt signaling mediator, β-catenin, might play an important role in CM differentiation from eEpi cells in culture.
Cytology and Genetics, 2015
Using conditional knockout animals, we studied the expression of the genes involved in the canonical Wnt signaling pathway (TCF 4, Axin 2) and the genes controlled by this signaling pathway (c fos, cyclin D1, c myc, and Cx43) in the myocardium of mice under the condition of embryonic cardio specific ablation of one allele of the β catenin gene. The inhibition of the canonical Wnt signaling was observed in all age groups tested (1, 3, and 6 months). An analysis of the genes controlled by the canonical Wnt pathway allowed us to reveal changes of their expression in the tissue of animals with cardiac specific β catenin hap loinsufficiency. The importance of a normally functioning canonical Wnt signaling for the growth and devel opment of the adult heart is especially underlined in the article.
Anatomy and Embryology, 1999
Previous research has revealed that cells contributing to coronary vascular formation are derived from the dorsal mesocardium, however, the fate of these cells during consecutive stages of heart development is still unclear. We have conducted a study regarding the recruitment of vascular components and the subsequent differentiation into mature vessel wall structures with the aid of immunohistochemical markers directed against endothelium, smooth muscle cells, and fibroblasts. The proepicardial organ including an adhering piece of primordial liver of quail embryos (ranging from HH15 to HH18) was transplanted into the pericardial cavity of chicken embryos (ranging from HH15 to HH18). The chicken-quail chimeras (n=16) were harvested from the early stage of endothelial tube formation (HH25) to the late stage of mature vessel wall composition (HH43). Before HH32 endothelial cells have invaded the myocardium to give rise to yet undifferentiated coronary vessels. These endothelial cells are not accompanied by other non-endothelial cells. The superficial epicardial layer changes from a squamous mesothelium into a cuboid epithelium preceding media and adventitia formation. Subsequently, a condensed area of mesenchymal cells delaminates from the cuboidal lining extending toward the vessel plexus. Around the coronary arteries, these mesenchymal cells differentiate into smooth muscle cells or fibroblasts as shown by immunohistochemical markers. We conclude that epithelial-mesenchymal transformation of the epicardial lining delivers the smooth muscle cells and fibroblasts of the coronary arterial vessel wall. Molecules involved in epithelial transformation processes elsewhere in the embryo are also expressed within the subepicardial layer, and are considered to participate in inducing this process.
Wnt/β-catenin-mediated signaling re-activates proliferation of matured cardiomyocytes
Stem Cell Research & Therapy
Background: The Wnt/β-catenin signaling pathway plays an important role in the development of second heart field (SHF Isl1+) that gives rise to the anterior heart field (AHF) cardiac progenitor cells (CPCs) for the formation of the right ventricle, outflow tract (OFT), and a portion of the inflow tract (IFT). During early cardiogenesis, these AHF CPCs reside within the pharyngeal mesoderm (PM) that provides a microenvironment for them to receive signals that direct their cell fates. Here, N-cadherin, which is weakly expressed by CPCs, plays a significant role by promoting the adhesion of CPCs within the AHF, regulating β-catenin levels in the cytoplasm to maintain high Wnt signaling and cardioproliferation while also preventing the premature differentiation of CPCs. On the contrary, strong expression of N-cadherin observed throughout matured myocardium is associated with downregulation of Wnt signaling due to β-catenin sequestration at the cell membrane, inhibiting cardioproliferation. As such, upregulation of Wnt signaling pathway to enhance cardiac tissue proliferation in mature cardiomyocytes can be explored as an interesting avenue for regenerative treatment to patients who have suffered from myocardial infarction. Methods: To investigate if Wnt signaling is able to enhance cellular proliferation of matured cardiomyocytes, we treated cardiomyocytes isolated from adult mouse heart and both murine and human ES cell-derived matured cardiomyocytes with N-cadherin antibody or CHIR99021 GSK inhibitor in an attempt to increase levels of cytoplasmic β-catenin. Immunostaining, western blot, and quantitative PCR for cell proliferation markers, cell cycling markers, and Wnt signaling pathway markers were used to quantitate re-activation of cardioproliferation and Wnt signaling. Results: N-cadherin antibody treatment releases sequestered β-catenin at N-cadherin-based adherens junction, resulting in an increased pool of cytoplasmic β-catenin, similar in effect to CHIR99021 GSK inhibitor treatment. Both treatments therefore upregulate Wnt signaling successfully and result in significant increases in matured cardiomyocyte proliferation. Conclusion: Although both N-cadherin antibody and CHIR99021 treatment resulted in increased Wnt signaling and cardioproliferation, CHIR99021 was found to be the more effective treatment method for human ES cell-derived cardiomyocytes. Therefore, we propose that CHIR99021 could be a potential therapeutic option for myocardial infarction patients in need of regeneration of cardiac tissue.
Journal of Molecular and Cellular Cardiology, 2007
In addition to its role in cell adhesion, β-catenin is an important signaling molecule in the Wnt/ Wingless signaling pathway. Recent studies have indicated that β-catenin is stabilized by hypertrophic stimuli and may regulate cardiac hypertrophic responses. To explore the role and requirement of β-catenin in cardiac development and hypertrophy, we deleted the β-catenin gene specifically in cardiac myocytes by crossing loxP-floxed β-catenin mice with transgenic mice expressing a Cre recombinase under the control of the α-myosin heavy chain promoter. No homozygous β-catenin deleted mice were born alive and died before embryonic day 14.5, indicating significant and irreplaceable roles of β-catenin in embryonic heart development. Heterozygous βcatenin deleted mice, however, demonstrated no structural and functional abnormality. The response of heterozygous β-catenin deleted mice to transverse aortic constriction, however, was significantly attenuated with decreased heart weight and heart weight/body weight ratio compared to controls with intact β-catenin genes. Hemodynamic analysis revealed that there was no difference in cardiac function between wild type and heterozygous β-catenin deleted mice. On the other hand, the expression of fetal genes, β-myosin heavy chain, atrial and brain natriuretic peptides was significantly higher in heterozygous β-catenin deleted mice when compared to wild type β-catenin mice. These results suggest that the cytoplasmic level of β-catenin modulates hypertrophic response and fetal gene reprogramming after pressure overload.
Wnt/β-Catenin Signaling during Cardiac Development and Repair
Journal of Cardiovascular Development and Disease, 2014
Active Wnt/β-catenin signaling is essential for proper cardiac specification, progenitor expansion and myocardial growth. During development, the mass of the embryonic heart increases multiple times to achieve the dimensions of adult ventricular chambers. Cell division in the embryonic heart is fairly present, whereas cell turnover in the adult myocardium is extremely low. Understanding of embryonic cardiomyocyte cell-replication, therefore, could improve strategies for cardiac regenerative therapeutics. Here, we review which role Wnt signaling plays in cardiac development and highlight a selection of attempts that have been made to modulate Wnt signaling after cardiac ischemic injury to improve cardiac function and reduce infarct size.