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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Induced Pluripotent Stem Cells
Drug Design
Cardiac Myocytes
Action Potentials
Romano-Ward Syndrome
Inborn Genetic Diseases
Drug Evaluation
Cardiac Arrhythmias
Phenotype
Gene Expression
Pharmaceutical Preparations
Genes
Proteins

Keywords

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

Cite this

Chen, Zhifen ; Xian, Wenying ; Bellin, Milena ; Dorn, Tatjana ; Tian, Qinghai ; Goedel, Alexander ; Dreizehnter, Lisa ; Schneider, Christine M. ; Ward-van Oostwaard, Dorien ; Ng, Judy King Man ; Hinkel, Rabea ; Pane, Luna Simona ; Mummery, Christine L. ; Lipp, Peter ; Moretti, Alessandra ; Laugwitz, Karl-Ludwig ; Sinnecker, Daniel. / Subtype-specific promoter-driven action potential imaging for precise disease modelling and drug testing in hiPSC-derived cardiomyocytes. In: European heart journal. 2016 ; Vol. 38, No. 4. pp. 292–301.
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title = "Subtype-specific promoter-driven action potential imaging for precise disease modelling and drug testing in hiPSC-derived cardiomyocytes",
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",
keywords = "Cardiomyocyte subtypes, Disease modelling, Optical action potential recordings, iPS cells",
author = "Zhifen Chen and Wenying Xian and Milena Bellin and Tatjana Dorn and Qinghai Tian and Alexander Goedel and Lisa Dreizehnter and Schneider, {Christine M.} and {Ward-van Oostwaard}, Dorien and Ng, {Judy King Man} and Rabea Hinkel and Pane, {Luna Simona} and Mummery, {Christine L.} and Peter Lipp and Alessandra Moretti and Karl-Ludwig Laugwitz and Daniel Sinnecker",
year = "2016",
doi = "10.1093/eurheartj/ehw189",
language = "English",
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pages = "292–301",
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Chen, Z, Xian, W, Bellin, M, Dorn, T, Tian, Q, Goedel, A, Dreizehnter, L, Schneider, CM, Ward-van Oostwaard, D, Ng, JKM, Hinkel, R, Pane, LS, Mummery, CL, Lipp, P, Moretti, A, Laugwitz, K-L & Sinnecker, D 2016, 'Subtype-specific promoter-driven action potential imaging for precise disease modelling and drug testing in hiPSC-derived cardiomyocytes' European heart journal, vol. 38, no. 4, pp. 292–301. https://doi.org/10.1093/eurheartj/ehw189

Subtype-specific promoter-driven action potential imaging for precise disease modelling and drug testing in hiPSC-derived cardiomyocytes. / Chen, Zhifen; Xian, Wenying; Bellin, Milena; Dorn, Tatjana; Tian, Qinghai; Goedel, Alexander; Dreizehnter, Lisa; Schneider, Christine M.; Ward-van Oostwaard, Dorien; Ng, Judy King Man; Hinkel, Rabea; Pane, Luna Simona; Mummery, Christine L.; Lipp, Peter; Moretti, Alessandra; Laugwitz, Karl-Ludwig; Sinnecker, Daniel.

In: European heart journal, Vol. 38, No. 4, 2016, p. 292–301.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Subtype-specific promoter-driven action potential imaging for precise disease modelling and drug testing in hiPSC-derived cardiomyocytes

AU - Chen, Zhifen

AU - Xian, Wenying

AU - Bellin, Milena

AU - Dorn, Tatjana

AU - Tian, Qinghai

AU - Goedel, Alexander

AU - Dreizehnter, Lisa

AU - Schneider, Christine M.

AU - Ward-van Oostwaard, Dorien

AU - Ng, Judy King Man

AU - Hinkel, Rabea

AU - Pane, Luna Simona

AU - Mummery, Christine L.

AU - Lipp, Peter

AU - Moretti, Alessandra

AU - Laugwitz, Karl-Ludwig

AU - Sinnecker, Daniel

PY - 2016

Y1 - 2016

N2 - 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

AB - 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

KW - Cardiomyocyte subtypes

KW - Disease modelling

KW - Optical action potential recordings

KW - iPS cells

U2 - 10.1093/eurheartj/ehw189

DO - 10.1093/eurheartj/ehw189

M3 - Article

VL - 38

SP - 292

EP - 301

JO - European heart journal

JF - European heart journal

SN - 0195-668X

IS - 4

ER -