Epicardial TGFβ and BMP Signaling in Cardiac Regeneration: What Lesson Can We Learn from the Developing Heart?

Abstract

The epicardium, the outer layer of the heart, has been of interest in cardiac research due to its vital role in the developing and diseased heart. During development, epicardial cells are active and supply cells and paracrine cues to the myocardium. In the injured adult heart, the epicardium is re-activated and recapitulates embryonic behavior that is essential for a proper repair response. Two indispensable processes for epicardial contribution to heart tissue formation are epithelial to mesenchymal transition (EMT), and tissue invasion. One of the key groups of cytokines regulating both EMT and invasion is the transforming growth factor β (TGFβ) family, including TGFβ and Bone Morphogenetic Protein (BMP). Abundant research has been performed to understand the role of TGFβ family signaling in the developing epicardium. However, less is known about signaling in the adult epicardium. This review provides an overview of the current knowledge on the role of TGFβ in epicardial behavior both in the development and in the repair of the heart. We aim to describe the presence of involved ligands and receptors to establish if and when signaling can occur. Finally, we discuss potential targets to improve the epicardial contribution to cardiac repair as a starting point for future investigation.

Keywords: BMP; EMT; Epicardium; TGFβ; cardiac development; cardiac repair; invasion.

Figure 1

Schematic overview of TGFβ family signaling. TGFβ family signaling can be divided into two clusters: TGFβ- (left) and BMP- (right) signaling. TGFβ1, -2 and -3 bind the TGFβ receptor II and activate signaling via type I receptor ALK5. Activin, nodal and inhibin can bind to the activin receptor IIA or IIB and propagate signaling via ALK4. Signaling via ALK4 and ALK5 leads to phosphorylation of SMAD2/3. Upon binding to SMAD4, this SMAD complex translocates to the nucleus to initiate gene transcription. Of note is that ALK7 (not displayed) can also initiate signaling via SMAD2/3, but this type I receptor is assumed to be unimportant in epicardial behavior. On the BMP side, BMPs can bind to either the activin receptor IIA or IIB, or to the BMP type II receptor, that can activate the signaling cascade via ALK2, -3 or -6, or via ALK1. Signaling via ALK1/2/3/6 results in phosphorylation of SMAD1/5/8 which, after binding to SMAD4, translocates to the nucleus and starts gene transcription. Besides the described SMAD-dependent pathways, both TGFβ and BMP pathways can activate SMAD-independent pathways, shown in the middle panel.

Figure 2

Schematic overview of epicardial behavior during development. Pro-epicardial cells migrate towards the heart and cover it to form the epicardium. When the epicardium has enveloped the heart, cells start to undergo epithelial to mesenchymal transition (EMT). This allows the epicardial derived cells to invade into the heart and differentiate into various cell types, mainly cardiac fibroblasts, smooth muscle cells, and pericytes. In addition, epicardial cells secrete paracrine factors that contribute to the development of the heart.

Figure 3

Schematic overview of TGFβ and Bone Morphogenetic Protein (BMP) signaling activity during the different stages of epicardial behavior. At the top, a timeline of epicardial activity is indicated, starting with the pro-epicardium (PE) and pro-epicardial migration towards the heart, followed by formation of the epicardium, epicardial EMT and invasion, subsequently epicardial quiescence in the healthy adult heart and ultimately the epicardial reactivation in the injured adult heart. For every stage, the known expression levels of ligands and receptors in vivo and in vitro are specified, based on the literature described in the main text. Expression levels determined in zebrafish are noted in italic. Based on the expression levels, a prediction of the activity of respectively TGFβ and BMP signaling over time is displayed by the curvature.