Abstract
In order to translate preclinical data into the clinical studies, relevant in vitro models with structure and key functional properties similar to native human tissue should be used. In vitro cardiac models with vascular structures mimic the highly vascularized myocardium and provide interactions between endothelial cells, stromal cells and cardiomyocytes. Currently, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have been shown to present immature morphology and fetal-like electrophysiological properties that may limit their use as physiological test platform. The aim of this study was to develop multicellular in vitro cardiovascular construct modeling human heart tissue. In the cardiovascular construct, hPSC-CMs were cultured with a vascular-like network formed by human foreskin fibroblasts and human umbilical vein endothelial cells that served as a platform in the construct. Cardiomyocyte orientation, maturation, electrophysiological properties and drug responses of the cardiovascular construct were characterized and compared to CM monoculture. hPSC-CMs in cardiovascular construct showed elongated morphology and aligned with the vascular-like network. Electrophysiological properties and calcium metabolism of hPSC-CMs as well as response to E-4031 and adrenaline demonstrated normal physiological behavior. Increased expression of cardiac structural proteins and ion channels in cardiovascular construct compared to CM monoculture were detected. In conclusion, vascular-like network supports the structural and functional maturation of hPSC-CMs. Our results suggest that cardiovascular construct presents more mature in vitro cardiac model compared to CM monoculture and could therefore serve as an advanced test system for cardiac safety and efficacy assessment as well as a model system for biomedical research.
Highlights
In adult heart, the majority of cardiac cells are highly adaptive cells including fibroblasts, vascular smooth muscle cells and endothelial cells. 20–40% of the cardiac cells are cardiomyocytes (Soonpaa and Field 1998; Brutsaert 2003)
Expression levels of angiogenesis related genes were analyzed at days 1, 6 and 18 in vascular-like network to assess the production of growth factors and maturation state of vascular structures (Fig. 2)
Significant increase was observed in angiopoietin 2 (Ang-2) and platelet derived growth factor b (PDGF-b) expression
Summary
The majority of cardiac cells are highly adaptive cells including fibroblasts, vascular smooth muscle cells and endothelial cells. 20–40% of the cardiac cells are cardiomyocytes (Soonpaa and Field 1998; Brutsaert 2003). Cells and ECM proteins, mainly produced by fibroblasts, are connected via cell–cell and cell– matrix interactions to maintain the structural organization and functionality of the heart (van Spreeuwel et al 2014; Pfannkuche et al 2010b). The interactions between vasculature and myocardium are bidirectional (Bhattacharya et al 2006), and active throughout the adult life affecting cardiac growth, function and rhythm (Brutsaert 2003). Endothelial cells and cardiomyocytes interact with each other with paracrine signals during heart development and activate the development of cardiac structure. This interaction is required for proper development of endocardium and myocardium.
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