Dataset Information

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

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.

SUBMITTER: Feyen DAM

PROVIDER: S-EPMC7437654 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Feyen Dries A M DAM McKeithan Wesley L WL Bruyneel Arne A N AAN Spiering Sean S Hörmann Larissa L Ulmer Bärbel B Zhang Hui H Briganti Francesca F Schweizer Michaela M Hegyi Bence B Liao Zhandi Z Pölönen Risto-Pekka RP Ginsburg Kenneth S KS Lam Chi Keung CK Serrano Ricardo R Wahlquist Christine C Kreymerman Alexander A Vu Michelle M Amatya Prashila L PL Behrens Charlotta S CS Ranjbarvaziri Sara S Maas Renee G C RGC Greenhaw Matthew M Bernstein Daniel D Wu Joseph C JC Bers Donald M DM Eschenhagen Thomas T Metallo Christian M CM Mercola Mark M

Cell reports 20200701 3

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 ...[more]

PMID: 32697997

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Project description:Cardiomyocytes differentiated from human embryonic stem cells (hESCs) represent a promising cell source for heart repair, disease modeling and drug testing. However, improving the differentiation efficiency and maturation of hESC-derived cardiomyocytes (hESC-CMs) is still a major concern. Retinoic acid (RA) signaling plays multiple roles in heart development. However, the effects of RA on cardiomyocyte differentiation efficiency and maturation are still unknown. Methods: RA was added at different time intervals to identify the best treatment windows for cardiomyocyte differentiation and maturation. The efficiency of cardiomyocyte differentiation was detected by quantitative real-time PCR and flow cytometry. Cardiomyocytes maturation was detected by immunofluorescence staining, metabolic assays and patch clamp to verify structural, metabolic and electrophysiological maturation, respectively. RNA sequencing was used for splicing analysis. Results: We found that RA treatment at the lateral mesoderm stage (days 2-4) significantly improved cardiomyocyte differentiation, as evidenced by the upregulation of TNNT2, NKX2.5 and MYH6 on day 10 of differentiation. In addition, flow cytometry showed that the proportion of differentiated cardiomyocytes in the RA-treated group was significantly higher than that in control group. RA treatment on days 15-20 increased cardiomyocyte area, sarcomere length, multinucleation and mitochondrial copy number. RNA sequencing revealed RA promoted RNA isoform switch to the maturation-related form. Meanwhile, RA promoted electrophysiological maturation and calcium handling of hESC-CMs. Importantly, RA-treated cardiomyocytes showed decreased glycolysis and enhanced mitochondrial oxidative phosphorylation, with the increased utilization of fatty acid and exogenous pyruvate but not glutamine. Conclusion: Our data indicated that RA treatment at an early time window (days 2-4) promotes the efficiency of cardiomyocyte differentiation and that RA treatment post beating (days 15-20) promotes cardiomyocyte maturation. The biphasic effects of RA provide new insights for improving cardiomyocyte differentiation and quality.

Dataset Information

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

Publications

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

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