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Human iPSC-derived cardiomyocytes: A comparison with primary cells and applications in standard and 3D culture models

Ventricular cardiac muscle cells, the cardiomyocytes, not to be confused with smooth muscle myocytes of the arterial wall or myoblasts of skeletal muscle, are the working muscle cells of the heart that relentlessly maintain the body’s circulation during a lifetime. Their high metabolic activity and low ischemic tolerance, sensitivity to changes in extracellular calcium, refractoriness to DNA transfection and limited lifespan in culture, notably without proliferation, make these cells a demanding in vitro model system. This issue is compounded by the absence of immortalized cell lines with characteristics comparable to primary human cardiomyocytes. The technology of reprograming somatic human cells into induced- pluripotent stem cells (hiPSC), which theoretically allows the production of cardiomyocytes and other cardiovascular cell types in unlimited amounts, has become popular as an alternative to primary rodent cells for disease modeling and toxicology. Furthermore, in vitro studies are now possible with hiPSC-derived cardiomyocytes from patients with specific disease-causing genotypes and genetic backgrounds, sometimes with access to their entire medical history.

Applications of hiPSC include general toxicology, drug efficacy and safety testing, cell physiology, disease modeling, 3D culture models and tissue engineering, and basic science. The only currently remaining concern with these cells is their comparably immature developmental state, showing features of the fetal or neonatal heart. In addition, there is heterogeneity in the cell population regarding expression patterns of different chambers of the heart or of the electrical conduction system. Also, some cellular features are less well formed such as T-tubules and the expression levels of connexins, depending on the properties of the original hiPSC-cell lines in comparison with the fully differentiated cells of the adult human heart. Several academic groups and companies are currently developing protocols and strategies to improve maturation and purity of hiPSC-derived cardiomyocytes. Our lab, at the University Hospital Bern, has been active in the field of cardio-toxicity for some years now, first with isolated cardiomyocytes from adult rats, using human samples from cardiac surgery, and now we are using hiPSC-derived cardiomyocytes from several commercial sources. As we are interested in the mechanisms of cancer therapy-associated cardiotoxicity, and want to study this in cardiomyocytes, we always endeavor to use the most relevant in vitro culture systems. Therefore, we have recently started to develop a 3D-culture model using hiPSC-derived cardiomyocytes and have tested this system in comparison with mature primary cells.

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