Cardiac microtissues from human pluripotent stem cells recapitulate the phenotype of long-QT syndrome

Biochemical and Biophysical Research Communications, vol. 572, pp. 118–124

Abstract

BACKGROUND: Human induced pluripotent stem cells (hiPSCs) and their derivative cardiomyocytes (hiPSC-CMs) have been successfully used to study the electrical phenotype of cardiac ion channel diseases. However, strategies to mature CMs and more comprehensive systems recapitulating the heart complexity are required to advance our ability to capture adult phenotypes. METHODS: We differentiated wild-type (WT) and long QT syndrome type 1 (LQT1) hiPSCs into CMs, endothelial cells and cardiac fibroblasts. The three cell types were combined to form three-dimensional (3D) spheroids, termed "cardiac microtissues" (cMTs) and the electrophysiological properties were measured using 96-well multi-electrode arrays. RESULTS: LQT1 cMTs displayed prolonged field potential duration compared to WT controls, thus recapitulating the typical feature of LQTS. Isoprenaline caused a positive chronotropic effect on both LQT1 and WT cMTs. The 96-well multi-electrode array format proved suitable to detect electrical changes directly in the 3D tissues. CONCLUSIONS: 3D hiPSC cMTs are a scalable tool that can be used to identify LQT electrical hallmarks and drug responses. We anticipate this tool can be adopted by pharmaceutical companies to screen cardio-active compounds.

Authors 4

1. Elisa Giacomelli Aachen Department of Anatomy and Embryology

   Memorial Sloan Kettering Cancer Center · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center (LUMC), 2333, ZA, Leiden, the Netherlands; The Center for Stem Cell Biology, Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA

   Department of Anatomy and Embryology, Leiden University Medical Center (LUMC), 2333, ZA, Leiden, the Netherlands

   The Center for Stem Cell Biology, Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA

2. Luca Sala Aachen Department of Anatomy and Embryology

   Leiden University Medical Center · IRCCS Istituto Auxologico Italiano

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center (LUMC), 2333, ZA, Leiden, the Netherlands; Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy

   Department of Anatomy and Embryology, Leiden University Medical Center (LUMC), 2333, ZA, Leiden, the Netherlands

   Istituto Auxologico Italiano IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy

3. Dorien Ward‐van Oostwaard Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center (LUMC), 2333, ZA, Leiden, the Netherlands

4. Milena Bellin corresponding Aachen Department of Anatomy and Embryology

   University of Padua · Leiden University Medical Center · Veneto Institute of Molecular Medicine

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center (LUMC), 2333, ZA, Leiden, the Netherlands; Department of Biology, University of Padua, 35121, Padua, Italy; Veneto Institute of Molecular Medicine, 35129, Padua, Italy. Electronic address: m.bellin@lumc.nl

   Department of Anatomy and Embryology, Leiden University Medical Center (LUMC), 2333, ZA, Leiden, the Netherlands

   Department of Biology, University of Padua, 35121, Padua, Italy

   Veneto Institute of Molecular Medicine, 35129, Padua, Italy