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.

Assembly of the Cardiac Pacemaking Complex: Electrogenic Principles of Sinoatrial Node Morphogenesis

“…While the functional role of BMPs and TGFbs has been extensively studied in the heart and is the subject of several excellent reviews (examples include [ 133 , 134 , 135 , 136 , 137 , 138 , 139 ]), we highlight some features of this pathway that may suggest their potential function in sinoatrial node morphogenesis.…”

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

“…Delineating the subtle mechanisms and cellular, molecular, and extracellular matrix players implicated in regenerative and non-regenerative hearts can provide insights into the homeostasisrepair-fibrosis continuum, which remains the most vexing challenge in developing successful regenerative/anti-fibrotic approaches for fibrotic disorders. Further, the refractory response of cardiomyocytes to complete cell-cycle progression through mitosis limits their self-renewal, therefore, cardiomyogenic approaches to treat heart failure remain practically intractable [38][39][40][41][42][43][44][45][46][47][48].…”

Bioengineering strategies to control epithelial-to-mesenchymal transition for studies of cardiac development and disease

“…The TGF-β superfamily is involved in a signaling network that regulates EMT and EndMT, 28,98 and it consists of a group of ligands that includes TGFβs, bone morphogenetic proteins (BMPs), activins, inhibins, and growth and differentiation factors. 78,99 Isoforms that activate signaling in EMT and EndMT include TGF-β1, 2, and 3, and BMP2 through BMP7, although they are associated differently with various EMT processes in development and disease and in various tissues, 59 including the heart. 78 Ligands of the TGF-β superfamily bind to a heterotetrameric receptor complex.…”

“… 78,99 Isoforms that activate signaling in EMT and EndMT include TGF-β1, 2, and 3, and BMP2 through BMP7, although they are associated differently with various EMT processes in development and disease and in various tissues, 59 including the heart. 78 Ligands of the TGF-β superfamily bind to a heterotetrameric receptor complex. 98 The TGF-β receptor complex transduces a signal through phosphorylation of SMAD transcription factors, which then bind to promoters of EMT and EndMT inducing genes in the nucleus, including the key transcription factor families SNAIL, TWIST, and ZEB.…”