Abstract
Current drug development efforts for the treatment of atrial fibrillation are hampered by the fact that many preclinical models have been unsuccessful in reproducing human cardiac physiology and its response to medications. In this study, we demonstrated an approach using human induced pluripotent stem cell‐derived atrial and ventricular cardiomyocytes (hiPSC‐aCMs and hiPSC‐vCMs, respectively) coupled with a sophisticated optical mapping system for drug screening of atrial‐selective compounds in vitro. We optimized differentiation of hiPSC‐aCMs by modulating the WNT and retinoid signaling pathways. Characterization of the transcriptome and proteome revealed that retinoic acid pushes the differentiation process into the atrial lineage and generated hiPSC‐aCMs. Functional characterization using optical mapping showed that hiPSC‐aCMs have shorter action potential durations and faster Ca2+ handling dynamics compared with hiPSC‐vCMs. Furthermore, pharmacological investigation of hiPSC‐aCMs captured atrial‐selective effects by displaying greater sensitivity to atrial‐selective compounds 4‐aminopyridine, AVE0118, UCL1684, and vernakalant when compared with hiPSC‐vCMs. These results established that a model system incorporating hiPSC‐aCMs combined with optical mapping is well‐suited for preclinical drug screening of novel and targeted atrial selective compounds.
Highlights
The advent of human induced pluripotent stem cell-derived cardiomyocytes has revolutionized the field of cardiac research
These results were later recapitulated in a pivotal study by Lee and Protze et al[6] who determined that atrial cardiomyocytes differentiated from human embryonic stem cells originate from a unique mesoderm characterized by robust retinaldehyde dehydrogenase 2 (RALDH2) expression
We developed a drug screening platform using human induced pluripotent stem cell-derived atrial cardiomyocytes and a multiwell optical mapping system
Summary
The advent of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has revolutionized the field of cardiac research. It has enabled the study of cardiac diseases in a patientspecific and human-relevant in vitro model system which provides a STEM CELLS Transl Med. 2020;1–15. Previous work in vivo has shown that the expression patterns of retinoic acid and retinaldehyde dehydrogenase 2 (RALDH2) are important determinants of the atrial fate.[2,3,4,5] These results were later recapitulated in a pivotal study by Lee and Protze et al[6] who determined that atrial cardiomyocytes (aCMs) differentiated from human embryonic stem cells (hESCs) originate from a unique mesoderm characterized by robust RALDH2 expression. Retinoic acid has been utilized to selectively differentiate hESCs and hiPSCs into aCMs in other studies.[6,7,8,9,10]
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