Endocardial and Epicardial Epithelial to Mesenchymal Transitions in Heart Development and Disease

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2012 Jun 9

PMID 22679138

Citations 199

Authors

Alexander von Gise

William T Pu

Affiliations

Soon will be listed here.

Abstract

Epithelial to mesenchymal transition (EMT) converts epithelial cells to mobile and developmentally plastic mesenchymal cells. All cells in the heart arise from one or more EMTs. Endocardial and epicardial EMTs produce most of the noncardiomyocyte lineages of the mature heart. Endocardial EMT generates valve progenitor cells and is necessary for formation of the cardiac valves and for complete cardiac septation. Epicardial EMT is required for myocardial growth and coronary vessel formation, and it generates cardiac fibroblasts, vascular smooth muscle cells, a subset of coronary endothelial cells, and possibly a subset of cardiomyocytes. Emerging studies suggest that these developmental mechanisms are redeployed in adult heart valve disease, in cardiac fibrosis, and in myocardial responses to ischemic injury. Redirection and amplification of disease-related EMTs offer potential new therapeutic strategies and approaches for treatment of heart disease. Here, we review the role and molecular regulation of endocardial and epicardial EMT in fetal heart development, and we summarize key literature implicating reactivation of endocardial and epicardial EMT in adult heart disease.

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References

Lin S, Dolle P, Ryckebusch L, Noseda M, Zaffran S, Schneider M . Endogenous retinoic acid regulates cardiac progenitor differentiation. Proc Natl Acad Sci U S A. 2010; 107(20):9234-9. PMC: 2889106. DOI: 10.1073/pnas.0910430107. View

Perez-Pomares J, de la Pompa J . Signaling during epicardium and coronary vessel development. Circ Res. 2011; 109(12):1429-42. DOI: 10.1161/CIRCRESAHA.111.245589. View

Ma L, Lu M, Schwartz R, Martin J . Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development. 2005; 132(24):5601-11. DOI: 10.1242/dev.02156. View

Itoh N, Ornitz D . Evolution of the Fgf and Fgfr gene families. Trends Genet. 2004; 20(11):563-9. DOI: 10.1016/j.tig.2004.08.007. View

Bock-Marquette I, Saxena A, White M, DiMaio J, Srivastava D . Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature. 2004; 432(7016):466-72. DOI: 10.1038/nature03000. View

Camenisch T, Molin D, Person A, Runyan R, Gittenberger-de Groot A, McDonald J . Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev Biol. 2002; 248(1):170-81. DOI: 10.1006/dbio.2002.0731. View

Grieskamp T, Rudat C, Ludtke T, Norden J, Kispert A . Notch signaling regulates smooth muscle differentiation of epicardium-derived cells. Circ Res. 2011; 108(7):813-23. DOI: 10.1161/CIRCRESAHA.110.228809. View

Combs M, Yutzey K . Heart valve development: regulatory networks in development and disease. Circ Res. 2009; 105(5):408-21. PMC: 2777683. DOI: 10.1161/CIRCRESAHA.109.201566. View

Itoh N, Ornitz D . Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J Biochem. 2010; 149(2):121-30. PMC: 3106964. DOI: 10.1093/jb/mvq121. View

10.

Hurlstone A, Haramis A, Wienholds E, Begthel H, Korving J, van Eeden F . The Wnt/beta-catenin pathway regulates cardiac valve formation. Nature. 2003; 425(6958):633-7. DOI: 10.1038/nature02028. View

11.

Tevosian S, Deconinck A, Tanaka M, Schinke M, Litovsky S, Izumo S . FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell. 2000; 101(7):729-39. DOI: 10.1016/s0092-8674(00)80885-5. View

12.

MacGrogan D, Luna-Zurita L, de la Pompa J . Notch signaling in cardiac valve development and disease. Birth Defects Res A Clin Mol Teratol. 2011; 91(6):449-59. DOI: 10.1002/bdra.20815. View

13.

von Gise A, Zhou B, Honor L, Ma Q, Petryk A, Pu W . WT1 regulates epicardial epithelial to mesenchymal transition through β-catenin and retinoic acid signaling pathways. Dev Biol. 2011; 356(2):421-31. PMC: 3147112. DOI: 10.1016/j.ydbio.2011.05.668. View

14.

Shirai M, Imanaka-Yoshida K, Schneider M, Schwartz R, Morisaki T . T-box 2, a mediator of Bmp-Smad signaling, induced hyaluronan synthase 2 and Tgfbeta2 expression and endocardial cushion formation. Proc Natl Acad Sci U S A. 2009; 106(44):18604-9. PMC: 2773962. DOI: 10.1073/pnas.0900635106. View

15.

Paranya G, Vineberg S, Dvorin E, Kaushal S, Roth S, Rabkin E . Aortic valve endothelial cells undergo transforming growth factor-beta-mediated and non-transforming growth factor-beta-mediated transdifferentiation in vitro. Am J Pathol. 2001; 159(4):1335-43. PMC: 1850524. DOI: 10.1016/s0002-9440(10)62520-5. View

16.

Duan J, Gherghe C, Liu D, Hamlett E, Srikantha L, Rodgers L . Wnt1/βcatenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. EMBO J. 2011; 31(2):429-42. PMC: 3261567. DOI: 10.1038/emboj.2011.418. View

17.

Zeisberg E, Kalluri R . Origins of cardiac fibroblasts. Circ Res. 2010; 107(11):1304-12. PMC: 3098499. DOI: 10.1161/CIRCRESAHA.110.231910. View

18.

Zeisberg E, Potenta S, Sugimoto H, Zeisberg M, Kalluri R . Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol. 2008; 19(12):2282-7. PMC: 2588112. DOI: 10.1681/ASN.2008050513. View

19.

Acloque H, Adams M, Fishwick K, Bronner-Fraser M, Nieto M . Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest. 2009; 119(6):1438-49. PMC: 2689100. DOI: 10.1172/JCI38019. View

20.

Smith C, Baek S, Sung C, Tallquist M . Epicardial-derived cell epithelial-to-mesenchymal transition and fate specification require PDGF receptor signaling. Circ Res. 2011; 108(12):e15-26. PMC: 3134964. DOI: 10.1161/CIRCRESAHA.110.235531. View