Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes

Dries A M Feyen; Wesley L McKeithan; Arne A N Bruyneel; Sean Spiering; Larissa Hörmann; Bärbel Ulmer; Hui Zhang; Francesca Briganti; Michaela Schweizer; Bence Hegyi; Zhandi Liao; Risto-Pekka Pölönen; Kenneth S Ginsburg; Chi Keung Lam; Ricardo Serrano; Christine Wahlquist; Alexander Kreymerman; Michelle Vu; Prashila L Amatya; Charlotta S Behrens; Sara Ranjbarvaziri; Renee G C Maas; Matthew Greenhaw; Daniel Bernstein; Joseph C Wu; Donald M Bers; Thomas Eschenhagen; Christian M Metallo; Mark Mercola

doi:10.1016/j.celrep.2020.107925

Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes

Cell Rep. 2020 Jul 21;32(3):107925. doi: 10.1016/j.celrep.2020.107925.

Authors

Dries A M Feyen¹, Wesley L McKeithan², Arne A N Bruyneel³, Sean Spiering⁴, Larissa Hörmann⁵, Bärbel Ulmer⁵, Hui Zhang⁶, Francesca Briganti³, Michaela Schweizer⁷, Bence Hegyi⁸, Zhandi Liao⁸, Risto-Pekka Pölönen⁸, Kenneth S Ginsburg⁸, Chi Keung Lam³, Ricardo Serrano³, Christine Wahlquist², Alexander Kreymerman³, Michelle Vu³, Prashila L Amatya³, Charlotta S Behrens⁵, Sara Ranjbarvaziri³, Renee G C Maas¹, Matthew Greenhaw³, Daniel Bernstein³, Joseph C Wu³, Donald M Bers⁸, Thomas Eschenhagen⁵, Christian M Metallo⁶, Mark Mercola⁹

Affiliations

¹ Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.
² Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA 94305, USA; Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, San Diego, CA, USA.
³ Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA 94305, USA.
⁴ Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, San Diego, CA, USA.
⁵ Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Department of Bioengineering, University of California, San Diego, San Diego, CA, USA.
⁷ Electron Microscopy Unit, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁸ Department of Pharmacology, University of California, Davis, Davis, CA, USA.
⁹ Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA 94305, USA; Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, San Diego, CA, USA. Electronic address: mmercola@stanford.edu.

Abstract

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have enormous potential for the study of human cardiac disorders. However, their physiological immaturity severely limits their utility as a model system and their adoption for drug discovery. Here, we describe maturation media designed to provide oxidative substrates adapted to the metabolic needs of human iPSC (hiPSC)-CMs. Compared with conventionally cultured hiPSC-CMs, metabolically matured hiPSC-CMs contract with greater force and show an increased reliance on cardiac sodium (Na⁺) channels and sarcoplasmic reticulum calcium (Ca²⁺) cycling. The media enhance the function, long-term survival, and sarcomere structures in engineered heart tissues. Use of the maturation media made it possible to reliably model two genetic cardiac diseases: long QT syndrome type 3 due to a mutation in the cardiac Na⁺ channel SCN5A and dilated cardiomyopathy due to a mutation in the RNA splicing factor RBM20. The maturation media should increase the fidelity of hiPSC-CMs as disease models.

Keywords: cardiomyocyte; dilated cardiomyopathy; disease modeling; engineered heart tissues; induced pluripotent stem cells; long QT syndrome 3; maturation; physiology.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Calcium / metabolism
Cardiac Conduction System Disease / genetics
Cardiac Conduction System Disease / physiopathology
Cardiomyopathy, Dilated / pathology
Cardiomyopathy, Dilated / physiopathology
Culture Media / pharmacology*
Gene Expression Regulation / drug effects
Heart / drug effects
Heart / physiopathology
Humans
Induced Pluripotent Stem Cells / cytology*
Induced Pluripotent Stem Cells / drug effects
Induced Pluripotent Stem Cells / metabolism*
Long QT Syndrome / genetics
Long QT Syndrome / physiopathology
Membrane Potentials / drug effects
Models, Biological
Myocardial Contraction / drug effects
Myocytes, Cardiac / cytology*
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism*
Phenotype
Tissue Engineering

Metabolic Maturation Media Improve Physiological Function of Human iPSC-Derived Cardiomyocytes

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