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Light-Activated Dynamic Clamp Using iPSC-Derived Cardiomyocytes
Journal Title
Biophysical Journal
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Publication Date
2018-12
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Publication Volume
115
Publication Issue
11
Publication Begin
2206
Publication End
2217
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PIIS0006349518311664.pdf
Adobe PDF, 3.13 MB
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Abstract
iPSC-derived cardiomyocytes (iPSC-CMs) are a potentially advantageous platform for drug screening because they provide a renewable source of human cardiomyocytes. One obstacle to their implementation is their immature electrophysiology, which reduces relevance to adult arrhythmogenesis. To address this, dynamic clamp is used to inject current representing the insufficient potassium current, IK1, thereby producing more adult-like electrophysiology. However, dynamic clamp requires patch clamp and is therefore low throughput and ill-suited for large-scale drug screening. Here, we use optogenetics to generate such a dynamic-clamp current. The optical dynamic clamp (ODC) uses outward-current-generating opsin, ArchT, to mimic IK1, resulting in more adult-like action potential morphology, similar to IK1 injection via classic dynamic clamp. Furthermore, in the presence of an IKr blocker, ODC revealed expected action potential prolongation and reduced spontaneous excitation. The ODC presented here still requires an electrode to measure Vm but provides a first step toward contactless dynamic clamp, which will not only enable high-throughput screening but may also allow control within multicellular iPSC-CM formats to better recapitulate adult in vivo physiology.
Citation
Quach B, Krogh-Madsen T, Entcheva E, Christini DJ. Light-Activated Dynamic Clamp Using iPSC-Derived Cardiomyocytes. Biophys J. 2018 Dec 4;115(11):2206-2217. doi: 10.1016/j.bpj.2018.10.018. Epub 2018 Oct 30. PMID: 30447994; PMCID: PMC6289097.