Elsevier

Differentiation

Volume 84, Issue 1, July 2012, Pages 41-53
Differentiation

The arterial and cardiac epicardium in development, disease and repair

https://doi.org/10.1016/j.diff.2012.05.002Get rights and content

Abstract

The importance of the epicardium covering the heart and the intrapericardial part of the great arteries has reached a new summit. It has evolved as a major cellular component with impact both in development, disease and more recently also repair potential. The role of the epicardium in development, its differentiation from a proepicardial organ at the venous pole (vPEO) and the differentiation capacities of the vPEO initiating cardiac epicardium (cEP) into epicardium derived cells (EPDCs) have been extensively described in recent reviews on growth and transcription factor pathways. In short, the epicardium is the source of the interstitial, the annulus fibrosus and the adventitial fibroblasts, and differentiates into the coronary arterial smooth muscle cells. Furthermore, EPDCs induce growth of the compact myocardium and differentiation of the Purkinje fibers. This review includes an arterial pole located PEO (aPEO) that provides the epicardium covering the intrapericardial great vessels. In avian and mouse models disturbance of epicardial outgrowth and maturation leads to a broad spectrum of cardiac anomalies with main focus on non-compaction of the myocardium, deficient annulus fibrosis, valve malformations and coronary artery abnormalities. The discovery that in disease both arterial and cardiac epicardium can again differentiate into EPDCs and thus reactivate its embryonic program and potential has highly broadened the scope of research interest. This reactivation is seen after myocardial infarction and also in aneurysm formation of the ascending aorta. Use of EPDCs for cell therapy show their positive function in paracrine mediated repair processes which can be additive when combined with the cardiac progenitor stem cells that probably share the same embryonic origin with EPDCs. Research into the many cell-autonomous and cell–cell-based capacities of the adult epicardium will open up new realistic therapeutic avenues.

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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