Subtype-specific promoter-driven action potential imaging for precise disease modelling and drug testing in hiPSC-derived cardiomyocytes

Zhifen Chen, Wenying Xian, Milena Bellin, Tatjana Dorn, Qinghai Tian, Alexander Goedel, Lisa Dreizehnter, Christine M. Schneider, Dorien Ward-van Oostwaard, Judy King Man Ng, Rabea Hinkel, Luna Simona Pane, Christine L. Mummery, Peter Lipp, Alessandra Moretti, Karl-Ludwig Laugwitz, Daniel Sinnecker

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Abstract

AIMS: Cardiomyocytes (CMs) generated from human induced pluripotent stem cells (hiPSCs) are increasingly used in disease modelling and drug evaluation. However, they are typically a heterogeneous mix of ventricular-, atrial-, and nodal-like cells based on action potentials (APs) and gene expression. This heterogeneity and the paucity of methods for high-throughput functional phenotyping hinder the full exploitation of their potential. We aimed at developing a method for rapid, sequential, and subtype-specific phenotyping of hiPSC-CMs with respect to AP morphology and single-cell arrhythmias.

METHODS AND RESULTS: We used cardiac lineage-specific promoters to drive the expression of a voltage-sensitive fluorescent protein (VSFP-CR) in hiPSC-CMs, enabling subtype-specific optical AP recordings. In a patient-specific hiPSC model of long-QT syndrome type 1, AP prolongation and frequent early afterdepolarizations were evident in mutant ventricular- and atrial like, but not in nodal-like hiPSC-CMs compared with their isogenic controls, consistent with the selective expression of the disease-causing gene. Furthermore, we demonstrate the feasibility of sequentially probing a cell over several days to investigate genetic rescue of the disease phenotype and to discern CM subtype-specific drug
Original languageEnglish
Pages (from-to)292–301
JournalEuropean heart journal
Volume38
Issue number4
DOIs
Publication statusPublished - 2016

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Keywords

  • Cardiomyocyte subtypes
  • Disease modelling
  • Optical action potential recordings
  • iPS cells

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