17 General Introduction and Thesis Outline 1 Table 1: Advantages and disadvantages in human iPSC-derived cardiomyocytes in vitro disease modeling platforms Model Advantage Disadvantages Format Costs Sensitivity Scalability EHTs Sensitivity to cardiotoxins, physiological force, and slow action potential Hypoxic conditions in center, risk of breaking. 24 wells High High Low Heart-on-a- chip Allows ECM manipulation, mimics 3D cardiac environment Limited imaging possibilities, Nonlinear cell alignment 48 wells Middle Middle Low Cardiac Spheroids Recapitulating cell-cell interactions, reproducible, small 3D model Lack of ECM, Nonlinear cell alignment. 384 wells Low Middle High Individual CMs Heterogeneity analyses, Strong proliferation capacity Far from physiological conditions, loss of cellcell interactions 384 wells Low Low Middle 2D Monolayers Action potential and calcium wave propagation measurements, IF Low on maturity, unable to recapitulate some disease phenotypes 384 wells Low Low High 1.7 High-throughput integrative disease modeling and drug screenings New therapies for genetic heart diseases have a high attrition rate, with only 1% reaching the stadium of a clinical trial.48 This low number can partly be explained in part by a reliance on animal models, transformed cell lines, and heterologous recombinant systems for drug discovery. Because of their ease of culture, cell-based assays used in drug screening have historically depended on animal cells. However, these cells are generally short-term cultured and are limited in how well they reflect human biology. Moreover, the use of more physiologically relevant primary cells is restricted by availability and inherent variability. As previously described, the advent of hiPSC technology has opened up the possibility of technology platforms to perform compound screens of hiPSC-derived cardiomyocytes with relatively high throughput. It is essential to realize their potential for drug discovery. To date, hiPSCs have been used to model a growing list of heart diseases, providing proof of concept that their differentiated derivatives can recapitulate disease-associated pathologies. Moreover, in some cases, it has been shown that pathologies expressed by these cell-based disease models can be ameliorated by drugs known to be therapeutic for patients.30 Based on an evaluation of multiple parameters including gene/mRNA/protein omics, mRNA/protein expression and electro-pathophysiology such as contractility and calcium handling, researchers will now be able to identify compounds that target molecules or pathways known to modulate cardiomyocytes, as well as those not previously associated with cardiomyocyte function
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