Cardiac organoid technology and computational processing of cardiac physiology for advanced drug screening applications

Stem cell technology has gained considerable recognition since its inception to advance disease modeling and drug screening. This is especially true for tissues that are difficult to study due to tissue sensitivity and limited regenerative capacity, such as the heart. Previous work in stem cell-derived cardiac tissue has exploited how we can engineer biologically functional heart tissue by providing the appropriate external stimuli to facilitate tissue development. The goal of this dissertation is to explore the potentials of stem cell cardiac organoid models to recapitulate heart development and implement analytical computational tools to study cardiac physiology. These new tools were implemented as potential advancements in drug screening applications for better predictions of drug-related cardiotoxicity. Cardiac organoids, generated via micropatterning techniques, were explored to determine how controlling engineering parameters, specifically the geometry, direct tissue fate and organoid function. The advantage of cardiac organoid models is the ability to recapitulate and study human tissue morphogenesis and development, which has currently been restricted through animal models. The cardiac organoids demonstrated responsiveness manifested as impairments to tissue formation and contractile functions as a result of developmental drug toxicity. Single-cell genomic characterization of cardiac organoids unveiled a co-emergence of cardiac and endoderm tissue, which is seen in vivo through paracrine signaling between the liver and heart. We then implemented computational tools based on nonlinear mathematical analysis to evaluate the cardiac physiological drug response of stem cell-derived cardiomyocytes. This dissertation discusses in vitro tissue platforms as well as computational tools to study drug-induced cardiotoxicity. Using these tools, we can extend current toolboxes of understanding cardiac physiology for advanced investigations of stem-cell based cardiac tissue engineering

Analysis of an Experimental Model of In Vitro Cardiac Tissue Using Phase Space Reconstruction

International audienceThe in vitro cultures of cardiac cells represent valuable models to study the mechanism of the arrhythmias at the cellular level. But the dynamics of these experimental models cannot be characterized precisely, as they include a lot of parameters that depend on experimental conditions. This paper is devoted to the investigation of the dynamics of an in vitro model using a phase space reconstruction. Our model, based on the heart cells of new born rats, generates electrical field potentials acquired using a microelectrode technology, which are analyzed in normal and under external stimulation conditions. Phase space reconstructions of electrical field potential signals in normal and arrhythmic cases are performed after characterizing the nonlinearity of the model, computing the embedding dimension and the time lag. A non-parametric statistical test (Kruskal-Wallis test) shows that the time lag $\tau$ could be used as an indicator to detect arrhythmia, while the embedding dimension is not significantly different between the normal and the arrhythmia cases. The phase space reconstructions highlight attractors, whose dimension reveals that they are strange, depicting a deterministic dynamics of chaotic nature in our in vitro model