The arterial and cardiac epicardium in development, disease and repair
Introduction
The epicardium covering both the heart and the intrapericardial part of the great arteries is subject to an intense revival of interest. Research on both morphological and functional characteristics including effective gene signaling pathways is booming as shown by a 10-fold increase in publications on the topic pro-epicardium between 2000 and 2011 and >3-fold on the topic epicardium development. Many reviews are currently available (Bollini et al., 2011, Lie-Venema et al., 2007, Limana et al., 2011, Manner et al., 2001, Martin-Puig et al., 2008, Olivey and Svensson, 2010, Perez-Pomares and Pompa, 2011, Riley and Smart, 2011, Smart et al., 2009, Smart and Riley, 2012, Wessels and Perez-Pomares, 2004, Winter and Gittenberger-de Groot, 2007a), presenting generally accepted data, but also aspects that are still controversial. Statements on the controversial issues are intriguing and trigger new research. In the current review the focus on the origin, fate, disease and repair provides novel insights in the potential of the epicardium. The epicardium cannot be regarded as a separate entity and is incorporated both structurally and functionally in the cardiac and vessel wall components. To support insight and structure of this review schematic Fig. 1 is instrumental.
Section snippets
Origin of the epicardium
The epicardium develops from the epithelium of the coelomic wall in close interaction with the underlying splanchnic mesoderm. With the formation of the intra-embryonic coelomic cavity, separating the intra-embryonic mesoderm into a splanchnic and a somatic layer, the splanchnic mesoderm lining the endoderm of the foregut develops into the bilateral cardiogenic plates. These are the precursors of the myocardial primary heart tube. This cardiogenic mesoderm is referred to as first heart field,
Epicardium derived cells (EPDCs)
After completed spreading of the epicardium over both the myocardium and the arterial pole the first wave of epithelial-to-mesenchymal transition (EMT) becomes apparent. Epicardial cells lose their epithelial contacts and EPDCs migrate into the subepicardial space (Gittenberger-de Groot et al., 1998, Lie-Venema et al., 2007, Manner, 1999). Many molecular pathways have been described to be essential for EMT including E-cadherin in relation to podoplanin (Mahtab et al., 2008), VCAM1 in relation
Heterogeneity and differentiation of the EPDCs
There is consensus on the differentiation potential of EPDCs into the interstitial cardiac fibroblasts, the coronary vascular smooth muscle cells and the adventitial fibroblasts. The initial data were derived from the study of the avian embryo by retroviral tracing and chicken–quail chimera studies (Dettman et al., 1998, Manner et al., 2001, Mikawa and Gourdie, 1996, Vrancken Peeters et al., 1999, Poelmann et al., 1993) and have been confirmed by transgenic mouse tracing studies with Gata5 (
The epicardium in congenital and adult cardiac disease
The epicardium is an essential population for proper development of the heart and great vessels. Complete inhibition of the outgrowth of the sinus venosus located vPEO leads to severe cardiac malformations (Gittenberger-de Groot et al., 2000). These include absence of vEP, aberrant and extensive outgrowth of aEP over the myocardial outflow tract, deficient looping with a wide inner curvature, absent ventricular and outflow tract septation and atrioventricular cushion formation, combined with a
Myocardial infarction
Based on the potential of the epicardium and EPDCs during normal development it is tempting to attribute a role in repair of the cardiac wall and its vascularization in various adult cardiac disease processes. The main cardiac disease studied in this respect is ischemic heart disease with subsequent myocardial fibrosis and heart failure. The primary cause is myocardial infarction (MI) after a coronary obstruction or occlusion due to atherosclerotic processes. If the epicardium and its EPDCs
Conclusion
In conclusion: The epicardium has acquired a dominant position in our understanding of proper cardiac development. Its effect is visible in most major processes including looping, myocardial maturation, septation, valve formation and coronary vascular development and patterning. A complicating factor in the study of the epicardium, using the current sophisticated mouse models, is that no specific genes for epicardium or EPDCs have been identified, as yet (Bochmann et al., 2010). Several reviews
Acknowledgments
We would like to thank Bert J Wisse for preparation of the figures and Ron Slagter for his excellent medical illustration work.
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