Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting over 33 million patients worldwide. It increases the risk of stroke, myocardial infarction, and heart failure, and requires therapy. Despite recent advances, current treatments have variable efficacy, in part because existing AF models do not fully recapitulate the real, AF-susceptible cellular substrate. The main challenge is that the induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs), which are increasingly used to model AF in the lab, are immature, often lacking the phenotypic maturity needed for effective drug screening and precision therapy development. Consequently, there is a critical need for better, more realistic models to understand AF and develop more precise therapies.

Addressing this, a recent study introduces a novel engineered coculture of iPSC-aCMs and atrial fibroblasts, offering a more representative model of AF, which is also suitable for high-throughput drug screening. The researchers developed a soft lithographic process to generate patterned cocultures of iPSC-aCMs and atrial fibroblasts within multiwell plates. Employing multiple assays, including optical voltage mapping, gene expression analysis, calcium imaging, automated patch clamp, and traction force microscopy, they then assessed the maturation of iPSC-aCMs in patterned coculture. The novel coculture significantly enhanced the structural, electrical, contractile, and metabolic maturity of iPSC-aCMs compared to traditional monoculture or coculture methods. Importantly, the presence of atrial, but not ventricular, fibroblasts played a crucial role in this enhanced maturation, likely mediated through specific molecular pathways involving connexin-40 and ephrin-B1.

The patterned coculture model showed greater sensitivity in detecting drug efficacy and was useful in modeling AF-like phenotypes, particularly in the context of a mutated SCN5A channel.

RNA sequencing revealed that iPSC-aCMs in the patterned coculture model had upregulated gene expression associated with muscle contraction, heart development, cell-cell adhesion, and other relevant pathways.

Interestingly, while patterned coculture significantly enhanced iPSC-aCM maturation compared to random monoculture, automated patch clamp recordings (performed with the SyncroPatch 384) showed that sodium current density was similar in both models, suggesting that some additional microenvironmental factors/stimuli could further mature iPSC-aCMs.

In conclusion, this study’s novel approach using engineered cocultures of iPSC-aCMs and atrial fibroblasts represents a significant advancement in modeling atrial fibrillation, enhancing our understanding of the disease and opening new avenues for the development of precision therapeutics.

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Find the original article here: https://www.science.org/doi/10.1126/sciadv.adg1222

Learn more about the SyncroPatch 384: https://www.nanion.de/products/syncropatch-384/