Researchers have developed a technique for growing human heart tissue, which can serve as an atrial model for clinical studies of arrhythmias.
Artificial tissue derived from human induced pluripotent stem cells (iPCSs) beats, expresses genes, and responds to drugs in the same way as the tissue of human real heart chambers. The model, described on November 8 in the journal Stem Cell Reports, may be used to evaluate the effectiveness of drugs in atrial fibrillation, the most common type of arrhythmia.
Unlike the standard two-dimensional culture, cardiomyocytes, derived from stem cells, were cultured under special conditions to form a 3D beating heart tissue resembling atrial heart muscle.
In particular, the cells showed contractile force, contraction and relaxation kinetics, electrophysiological properties, pharmacological responses to specific selective drugs, and atrial gene expression.
According to the authors of the study, constructed heart tissue can be used for both mechanistic studies of arrhythmias and preclinical screening of drugs.
“This is the first time that human atrial heart tissue has been generated in vitro from a principally unlimited source of hiPSCs”, – says first author Marta Lemme of the University Medical Center Hamburg-Eppendorf. “This could be useful both for academic laboratories and the pharmaceutical industry, because to test potential new drugs, we need to generate an in vitro model of atrial fibrillation. And the first step in that is to obtain cells that resemble human atrial cardiomyocytes”.
Lemme and senior study author Thomas Eschenhagen of the University Medical Center Hamburg-Eppendorf decided to achieve this goal by creating atrial-like cardiomyocytes from iPSCs using a vitamin A metabolite known as all-trans retinoic acid.
This method includes the genetic reprogramming blood or skin cells obtained from human donors to an embryonic stem-cell-like state. Then, the resulting immature cells are treated with all-trans retinoic acid to convert them into atrial-like cardiomyocytes.
“But the novelty of this study is the combination of hiPSC differentiation into atrial cardiomyocytes with a 3D environment”, – Lemme says. “In fact, we showed that the 3D environment favors the differentiation toward an atrial phenotype compared to standard 2D culture. A particular value of our study is the direct comparison of our 3D engineered heart tissue with native human atrial tissue obtained from patients on a molecular and functional level”.
More than 33 million people worldwide suffer from atrial fibrillation. And this number is constantly growing. A fast irregular atrial rhythm increases the risk of blood clots, which can lead to stroke and heart failure.
Unluckily, existing treatments, such as antiarrhythmic drugs, have limited effectiveness and can have side effects. In addition, the development of new drugs is complicated by the difficulties of isolating and maintaining a viable culture of human atrial cardiomyocytes (or cardiac muscle cells). Animal models have limited predictive power because they do not accurately represent the physiology of human cardiomyocytes.
“These atrial muscle strips represent a great opportunity to model atrial fibrillation in the dish and test drugs”, – Lemme says.
“Nevertheless, improvements can still be made to reach even higher similarity with the human atrial tissue. For us, the next step is to test various means to induce arrhythmias, study mechanisms of electrical remodeling of atrial fibrillation and test new potential drugs.”