Researchers have developed a way to grow human cardiac tissue that can serve as a model for the upper heart chambers, known as atria. Tissue, derived from human pluripotent stem cells (hiPCS), beats, expresses genes and responds to drugs in a similar way to a real human atrium. A model he described on November 8 in the magazine Stem Cell Reports, may be useful for assessing disease mechanisms and the drugs for atrial fibrillation – the most common type of arrhythmia.
Unlike standard 2D culture, cardiomyocytes derived from stem cells were cultured to produce 3D abrasive heart tissue reminiscent of atrial heart muscle. Specifically, the cells exhibited atrial forms of gene expression, contractile force, contraction and relaxation kinetics, electrophysiological properties and pharmacological responses to atrial-selective drugs. According to the authors, engineering cardiac tissue could serve as a model of the human atrium for both mechanical atrial fibrillation studies and preclinical drug screening.
"This is the first time that human atrial heart tissue was generated in vitro from an unlimited source of hiPSC," says Marta Lemme of the University Medical Center Hamburg-Eppendorf. "This could be useful for both academic laboratories and the pharmaceutical industry, because in order to test potential new drugs, we need to generate an in vitro model of atrial fibrillation and the first step is to obtain cells that resemble human cardiac cardiomyocytes," says Lemme.
Lemme and lead researcher Thomas Eschenhagen of the University Medical Center Hamburg-Eppendorf have decided to achieve this goal by creating atrial cardiomyocytes from hiPSC using the vitamin A metabolite called trans-retinoic acid. This technique involves the genetic reprogramming of blood or skin cells taken from human donors into a state similar to embryonic stem cells and subsequent treatment of these immature cells with all-trans retinoic acid for their conversion to atrial-like cardiomyocytes.
"But the novelty of this study is a combination of hiPSC differentiation with atrial cardiomyocytes with a 3D environment," Lemme says. "In fact, we have shown that the 3D environment promotes differentiation to the atrial phenotype compared to standard 2D culture." "The special value of our study is the direct comparison of our 3D-engineered heart with native human atrial tissue obtained from patients to molecular and functional levels.
Over 33 million people worldwide suffer from atrial fibrillation and prevalence is rising. Uncoordinated high-frequency contractions in the forehead increase the risk of blood clots, stroke and heart failure. Unfortunately, existing treatments such as antiarrhythmic drugs have limited efficacy and may have undesirable effects. Additionally, the development of new drugs has been slowed by difficulties in the isolation and maintenance of human cardiac cardiomyocytes or heart muscle cells. Animal models have limited predictive power because they do not represent the exact physiology of human cardiomyocytes.
"These breast atrial muscles are a great opportunity to model atrial fibrillation in bowls and tested drugs," says Lemme. "We still have to improve the attainment of an even higher resemblance to human atrial tissue, and we are testing a variety of ways to induce arrhythmia, study the mechanisms of electrical remodeling of atrial fibrillation, and test new potential drugs."
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