Modeling an Excitable Biosynthetic Tissue with Inherent Variability for Paired Computational-Experimental Studies

To understand how excitable tissues give rise to arrhythmias, it is crucially necessary to understand the electrical dynamics of cells in the context of their environment. Multicellular monolayer cultures have proven useful for investigating arrhythmias and other conduction anomalies, and because of their relatively simple structure, these constructs lend themselves to paired computational studies that often help elucidate mechanisms of the observed behavior. However, tissue cultures of cardiomyocyte monolayers currently require the use of neonatal cells with ionic properties that change rapidly during development and have thus been poorly characterized and modeled to date. Recently, Kirkton and Bursac demonstrated the ability to create biosynthetic excitable tissues from genetically engineered and immortalized HEK293 cells with well-characterized electrical properties and the ability to propagate action potentials. In this study, we developed and validated a computational model of these excitable HEK293 cells (called “Ex293” cells) using existing electrophysiological data and a genetic search algorithm. In order to reproduce not only the mean but also the variability of experimental observations, we examined what sources of variation were required in the computational model. Random cell-to-cell and inter-monolayer variation in both ionic conductances and tissue conductivity was necessary to explain the experimentally observed variability in action potential shape and macroscopic conduction, and the spatial organization of cell-to-cell conductance variation was found to not impact macroscopic behavior; the resulting model accurately reproduces both normal and drug-modified conduction behavior. The development of a computational Ex293 cell and tissue model provides a novel framework to perform paired computational-experimental studies to study normal and abnormal conduction in multidimensional excitable tissue, and the methodology of modeling variation can be applied to models of any excitable cell.Author Summary: One of the major challenges in trying to understand how arrhythmias can form in cardiac tissue is studying how the electrical activity of cardiac cells is affected by their surroundings. Current approaches have focused on studying cardiac cells in vitro and using computational models to elucidate the mechanisms behind experimental findings. However, tissue culture techniques are limited to working with neonatal, rather than adult, cells, and computational modeling of these cells has proven challenging. In this work, we have a developed a new approach for conducting paired experimental and computational studies by using a cell line engineered with the minimum machinery for excitability, and a computational model derived and validated directly from this cell line. In order to create a model that reproduces the diversity, rather than simply the average behavior, of experimental studies, we have incorporated a simple yet novel method of inherent variability, and explored what types of experimental variation must be incorporated into the model to recapitulate experimental findings. Using this new platform for paired experimental-computational studies with inherent variability, we will be able to study and better understand how changes in cardiac structure such as fibrosis and heterogeneity lead to conduction slowing, conduction failure, and arrhythmogenesis.