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

• Published in: Cell reports (Cambridge) Vol. 32; no. 3; p. 107925
• Main Authors: Feyen, Dries A.M., McKeithan, Wesley L., Bruyneel, Arne A.N., Spiering, Sean, Hörmann, Larissa, Ulmer, Bärbel, Zhang, Hui, Briganti, Francesca, Schweizer, Michaela, Hegyi, Bence, Liao, Zhandi, Pölönen, Risto-Pekka, Ginsburg, Kenneth S., Lam, Chi Keung, Serrano, Ricardo, Wahlquist, Christine, Kreymerman, Alexander, Vu, Michelle, Amatya, Prashila L., Behrens, Charlotta S., Ranjbarvaziri, Sara, Maas, Renee G.C., Greenhaw, Matthew, Bernstein, Daniel, Wu, Joseph C., Bers, Donald M., Eschenhagen, Thomas, Metallo, Christian M., Mercola, Mark
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.07.2020
• Subjects: Calcium - metabolism; Cardiac Conduction System Disease - genetics; Cardiac Conduction System Disease - physiopathology; cardiomyocyte; Cardiomyopathy, Dilated - pathology; Cardiomyopathy, Dilated - physiopathology; Culture Media - pharmacology; dilated cardiomyopathy; disease modeling; engineered heart tissues; Gene Expression Regulation - drug effects; Heart - drug effects; Heart - physiopathology; Humans; induced pluripotent stem cells; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Long QT Syndrome - genetics; Long QT Syndrome - physiopathology; long QT syndrome 3; maturation; Membrane Potentials - drug effects; Models, Biological; Myocardial Contraction - drug effects; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Phenotype; physiology; Tissue Engineering; maturation; cardiomyocyte; disease modeling; physiology; long QT syndrome 3; induced pluripotent stem cells; engineered heart tissues; dilated cardiomyopathy
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107925

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. [Display omitted] •We developed a defined maturation medium for hiPSC-CMs•The media improve electrophysiological and mechanical characteristics of hiPSC-CMs•The media improve the fidelity of disease modeling Physiological immaturity of iPSC-derived cardiomyocytes limits their fidelity as disease models. Feyen et al. developed a low glucose, high oxidative substrate media that increase maturation of ventricular-like hiPSC-CMs in 2D and 3D cultures relative to standard protocols. Improved characteristics include a low resting Vm, rapid depolarization, and increased Ca2+ dependence and force generation.