Human Cardiac Ventricular‐Like Organoid Chambers and Tissue Strips From Pluripotent Stem Cells as a Two‐Tiered Assay for Inotropic Responses

Abstract

Traditional drug discovery is an inefficient process. Human pluripotent stem cell‐derived cardiomyocytes can potentially fill the gap between animal and clinical studies, but conventional two‐dimensional cultures inadequately recapitulate the human cardiac phenotype. Here, we systematically examined the pharmacological responses of engineered human ventricular‐like cardiac tissue strips (hvCTS) and organoid chambers (hvCOC) to 25 cardioactive compounds covering various drug classes. While hvCTS effectively detected negative and null inotropic effects, the sensitivity to positive inotropes was modest. We further quantified the predictive capacity of hvCTS in a blinded screening, with accuracies for negative, positive, and null inotropic effects at 100%, 86%, and 80%, respectively. Interestingly, hvCOC, with a pro‐maturation milieu that yields physiologically complex parameters, displayed enhanced positive inotropy. Based on these results, we propose a two‐tiered screening system for avoiding false positives and negatives. Such an approach would facilitate drug discovery by leading to better overall success.

Dynamic Loading of Human Engineered Heart Tissue Enhances Contractile Function and Drives Desmosome-linked Disease Phenotype

“…The dyn-EHT platform builds off of previous work from our laboratory and other investigators that have used primary, hESC and hiPSC derived cardiomyocytes to engineer functional cardiac tissues in vitro. Indeed, it is critical to acknowledge the important contributions to the field made by researchers using EHTs to model development and disease, and implementing more physiologic-like electromechanical conditioning to drive maturation (14,(16)(17)20,23,(25)(26)28,40,(61)(62)(63)(64). However, these 2D and 3D EHTs are generally isometrically constrained, which means they are unable to undergo significant fractional shortening or be stretched by preload.…”

“…Further, strategies aimed at reducing the ventricular wall stress by integrating a temporary patch over the myocardial infarct (58) or injecting materials to thicken the ventricle wall (59) have proved successful to combat the pathological remodeling observed following myocardial infarction. While there have been recent advances in engineering ventricle-like chambers using scaffolds and 3D bioprinting (22,(60)(61)(62), compared to our dyn-EHT these chambers are much more difficult to fabricate, require a relatively large number of cells to form, and must be connected to a complicated flow system with valves and pressure transducers in order to generate preload.…”

Human Pluripotent Stem Cells for Modeling of Anticancer Therapy-Induced Cardiotoxicity and Cardioprotective Drug Discovery

“…The simpler form is cardiac organoid, which involves self-aggregation of hiPSC-CMs and or other cell types into spherical organoids in 3D with cellular organization comparable to native heart tissue and which can assess parameters such as cell viability and cytotoxicity (Polonchuk et al, 2017). A more sophisticated type of 3D tissue is engineered cardiac tissue which involves tight control of cellular organization with specific scaffold materials and cell density (Mannhardt et al, 2017a;Keung et al, 2019). The improved alignment of these engineered tissue constructs yields more mature cells and more physiologically relevant functional assessment capabilities that can be adapted to high throughput and high content assays, including true twitch forces, pressure-volume relationships, stroke work and macroelectrophysiological parameters (Mannhardt et al, 2017b;Li et al, 2018;Keung et al, 2019).…”

“…A more sophisticated type of 3D tissue is engineered cardiac tissue which involves tight control of cellular organization with specific scaffold materials and cell density (Mannhardt et al, 2017a;Keung et al, 2019). The improved alignment of these engineered tissue constructs yields more mature cells and more physiologically relevant functional assessment capabilities that can be adapted to high throughput and high content assays, including true twitch forces, pressure-volume relationships, stroke work and macroelectrophysiological parameters (Mannhardt et al, 2017b;Li et al, 2018;Keung et al, 2019). For example, in a recent study using a form of 3D microtissue to model cardiotoxicity, the authors were able to demonstrate an increase in afterload on cardiomyocytes with increased sunitinibinduced cardiotoxicity, highlighting the superiority of 3D models to assess more complex physiological parameters which are not feasible with 2D culture models (Truitt et al, 2018).…”

Induced pluripotent stem cells for therapy personalization in pediatric patients: Focus on drug-induced adverse events

“…Fluid-ejecting 3D human ventricular-like cardiac organoid chambers (hvCOC) can mimic physiologically complex behaviors, such as pressure-volume relationships, and have been used for detecting contractile responses to different pharmacological compounds[127,128]. The hvCOC system can accurately identify inotropic effects of pharmacological compounds such as isoproterenol and levosimendan, with increased sensitivity with respect to human ventricular-like cardiac tissues strips.…”