Cardiomyocyte-Endothelial Cell Interactions in Cardiac Remodeling and Regeneration

Abstract

The heart is a complex organ consisting of various cell types, each of which plays an important role in both physiological and pathophysiological conditions. The cells communicate with each other through direct cell-cell interactions and paracrine signaling, and both homotypic and heterotypic cell interactions contribute to the organized structure and proper function of the heart. Cardiomyocytes (CMs) and endothelial cells (ECs) are two of the most abundant cardiac cell types and they also play central roles in both cardiac remodeling and regeneration. The postnatal cell cycle withdrawal of CMs, which takes place within days or weeks after birth, represents the major barrier for regeneration in adult mammalian hearts, as adult CMs exhibit a very low proliferative capacity. Recent evidence highlights the importance of ECs not only as the most abundant cell type in the heart but also as key players in post-infarction remodeling and regeneration. In this MiniReview, we focus on blood vascular ECs and CMs and their roles and interactions in cardiac physiology and pathologies, with a special emphasis on cardiac regeneration. We summarize the known mediators of the bidirectional CM-EC interactions and discuss the related recent advances in the development of therapies aiming to promote heart repair and regeneration targeting these two cell types.

Keywords: cardiac cell therapy; cardiac regeneration; cardiac remodeling; cardiomyocyte; cardiovascular gene therapy; cell-cell interaction; endothelial cell.

Figure 1

The main cardiac cell types and their interactions with endothelial cells and cardiomyocytes. Selected known paracrine factors mediating endothelial cell—cardiomyocyte cross-talk (angiocrines and cardiokines) are illustrated. The relative abundances of each cell type in normal adult mouse ventricular tissue are from (6) and represent those quantified in adult mouse heart. Solid arrows represent well known cell-cell interactions and dashed lines illustrate less well characterized but potentially important interactions. ET-1, endothelin-1; FGFs, fibroblast growth factors; FST, follistatin; FSTL1, follistatin-like 1; HGF, hepatocyte growth factor; NO, nitric oxide; VEGFs, vascular endothelial growth factors.

Figure 2

Therapeutic approaches targeting cardiomyocytes and endothelial cells to promote cardiac regeneration and repair. Gene therapies to induce revascularization and cardiac regeneration are being investigated using various approaches, including adeno-associated (AAV) and adenoviral vectors, as well as modified RNAs (modRNAs). Potential regenerative drug therapies that are in preclinical stages of drug discovery and development include small molecule compounds and biologics such as growth factors. Cell therapies include the use of stem cells, cardiovascular progenitor cells and stem cell-derived cardiovascular cells to repair the damaged myocardium. Tissue engineering approaches use stem cell-derived cardiomyocytes and other cell types to create organized tissue patches for transplantation. hPSC, human pluripotent stem cell; hPSC-CMs, hPSC-derived cardiomyocytes; hPSC-ECs, hPSC-derived endothelial cells; hPSC-SMCs, hPSC-derived smooth muscle cells; hPSC-FBs, hPSC-derived fibroblasts.