The Arterial Epicardium: A Developmental Approach to Cardiac Disease and Repair

Abstract

The significance of the epicardium that covers the heart and the roots of the great arteries should not be underestimated as it is a major component with impact on development, disease, and repair. The epicardium differentiates from the proepicardial organ located at the venous pole (vPEO). The differentiation capacities of the vPEO into epicardium-derived cells (EPDCs) have been extensively described. A hitherto escaped part of the epicardium derives from a second proepicardial organ located at the arterial pole (aPEO) and covers the intrapericardial part of the aorta and pulmonary trunk. In avian and mouse embryos, disturbance of epicardium differentiation causes a spectrum of cardiac anomalies including coronary artery abnormalities, deficient annulus fibrosis with rhythm disturbances, valve malformations, and non-compaction cardiomyopathies. Late in prenatal life the epicardium becomes dormant, losing the activity of many genes.In human cardiac diseases, both arterial and venous epicardium can be activated again into EPDCs. The epicardial reactivation observed after experimental

Keratin 19 (Krt19) is a novel marker gene for epicardial cells

“…The epicardium is well known to serve not only as a reservoir of multipotential progenitor cells but also as a crucial source of mitogenic signals orchestrating heart development ( Ruiz-Villalba and Perez-Pomares, 2012 ; Simoes and Riley, 2018 ; Cao et al, 2020 ). Anomalies in epicardial development and their signaling mechanisms in diverse mouse models manifest as defective cardiac development, mirroring human CHDs ( Ruiz-Villalba and Perez-Pomares, 2012 ; Gittenberger-de Groot et al, 2016 ). Notably, the primary CHD arising from aberrant epicardium is left ventricular non-compaction cardiomyopathy, with additional implications for coronary vascular anomalies, valvulopathies, and conduction system anomalies ( Zhang et al, 2013 ; Gittenberger-de Groot et al, 2016 ).…”

“…Anomalies in epicardial development and their signaling mechanisms in diverse mouse models manifest as defective cardiac development, mirroring human CHDs ( Ruiz-Villalba and Perez-Pomares, 2012 ; Gittenberger-de Groot et al, 2016 ). Notably, the primary CHD arising from aberrant epicardium is left ventricular non-compaction cardiomyopathy, with additional implications for coronary vascular anomalies, valvulopathies, and conduction system anomalies ( Zhang et al, 2013 ; Gittenberger-de Groot et al, 2016 ). Consequently, undertaking a systematic inquiry into the function of the epicardium becomes imperative, promising valuable insights into the mechanisms underlying CHDs.…”

Generation, Characterization, and Application of Inducible Proliferative Adult Human Epicardium-Derived Cells

“…Given the ability of EPDCs to (i) contribute to different cardiac cell lineages, (ii) produce beneficial paracrine factors for heart development and (iii) recapitulate an embryonic epicardial phenotype after cardiac damage in adult hearts, they are a highly interesting study object from a cardiac developmental and regenerative perspective. An increased understanding of epicardial cell properties and behavior could not only provide new insights into certain (congenital) heart diseases but also generate additional knowledge about the ability of epicardial cells to participate in human cardiac repair [9,10]. Our research group has previously established cell culture models based on primary human EPDCs that allowed us to investigate processes like EMT [11][12][13].…”