Importance of myocyte-nonmyocyte interactions in cardiac development and disease

Abstract

Emerging data in the field of cardiac development as well as repair and regeneration indicate a complex and important interplay between endocardial, epicardial, and myofibroblast populations that is critical for cardiomyocyte differentiation and postnatal function. For example, epicardial cells have been shown to generate cardiac myofibroblasts and may be one of the primary sources for this cell lineage during development. Moreover, paracrine signaling from the epicardium and endocardium is critical for proper development of the heart and pathways such as Wnt, fibroblast growth factor, and retinoic acid signaling have been shown to be key players in this process. Despite this progress, interactions between nonmyocyte cells and cardiomyocytes in the heart are still poorly understood. We review the various nonmyocyte-myocyte interactions that occur in the heart and how these interactions, primarily through signaling networks, help direct cardiomyocyte differentiation and regulate postnatal cardiac function.

Figure 1. Model of reciprocal signaling between endocardial cells and myocytes during cardiac development, growth, and maturation

(A) Depiction of this reciprocal signaling during myocardial trabeculation. (B) The left side depicts myocardial-endocardial signaling while the right side depicts endocardial-myocardial signaling. (C) Depiction of this signaling during endocardial cushion formation. (D) Major signaling pathways regulating endocardial-mesenchymal transformation (EMT).

Figure 2. Model of interactions between epicardium and myocardium in cardiac development

(A) A schematic depiction of epicardium-myocardium communication. Epicardial progenitors undergo an epithelial-to-mesenchymal transition, invade the myocardium, and differentiate into various mature cardiac cell types, including vascular smooth muscle cells, endothelial cells, fibroblasts and cardiac myocytes.(B) Important signaling pathways regulating this process are shown. The left side (pink) depicts the signaling within epicardium, the middle side (yellow) depicts how epicardium influences myocardial proliferation, while the right side (blue) depicts myocardium regulating epicardial development and function.