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Editorial published on 15 January 2020, see Cells 2020, 9(1), 213.
Article

Fatty Acid-Treated Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes Exhibit Adult Cardiomyocyte-Like Energy Metabolism Phenotypes

1
Department of Emergency Medicine, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan
2
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
3
Department of Cell Biology, Neuroscience & Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
4
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
5
Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
6
Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Tokyo 113-8421, Japan
7
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
*
Author to whom correspondence should be addressed.
Cells 2019, 8(9), 1095; https://doi.org/10.3390/cells8091095
Received: 5 April 2019 / Revised: 12 September 2019 / Accepted: 14 September 2019 / Published: 17 September 2019
(This article belongs to the Special Issue Stem Cell-based Therapy and Disease Modeling)
Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) (iPSC-CMs) are a promising cell source for myocardial regeneration, disease modeling and drug assessment. However, iPSC-CMs exhibit immature fetal CM-like characteristics that are different from adult CMs in several aspects, including cellular structure and metabolism. As an example, glycolysis is a major energy source for immature CMs. As CMs mature, the mitochondrial oxidative capacity increases, with fatty acid β-oxidation becoming a key energy source to meet the heart’s high energy demand. The immaturity of iPSC-CMs thereby limits their applications. The aim of this study was to investigate whether the energy substrate fatty acid-treated iPSC-CMs exhibit adult CM-like metabolic properties. After 20 days of differentiation from human iPSCs, iPSC-CMs were sequentially cultured with CM purification medium (lactate+/glucose-) for 7 days and maturation medium (fatty acids+/glucose-) for 3–7 days by mimicking the adult CM’s preference of utilizing fatty acids as a major metabolic substrate. The purity and maturity of iPSC-CMs were characterized via the analysis of: (1) Expression of CM-specific markers (e.g., troponin T, and sodium and potassium channels) using RT-qPCR, Western blot or immunofluorescence staining and electron microscopy imaging; and (2) cell energy metabolic profiles using the XF96 Extracellular Flux Analyzer. iPSCs-CMs (98% purity) cultured in maturation medium exhibited enhanced elongation, increased mitochondrial numbers with more aligned Z-lines, and increased expression of matured CM-related genes, suggesting that fatty acid-contained medium promotes iPSC-CMs to undergo maturation. In addition, the oxygen consumption rate (OCR) linked to basal respiration, ATP production, and maximal respiration and spare respiratory capacity (representing mitochondrial function) was increased in matured iPSC-CMs. Mature iPSC-CMs also displayed a larger change in basal and maximum respirations due to the utilization of exogenous fatty acids (palmitate) compared with non-matured control iPSC-CMs. Etomoxir (a carnitine palmitoyltransferase 1 inhibitor) but not 2-deoxyglucose (an inhibitor of glycolysis) abolished the palmitate pretreatment-mediated OCR increases in mature iPSC-CMs. Collectively, our data demonstrate for the first time that fatty acid treatment promotes metabolic maturation of iPSC-CMs (as evidenced by enhanced mitochondrial oxidative function and strong capacity of utilizing fatty acids as energy source). These matured iPSC-CMs might be a promising human CM source for broad biomedical application. View Full-Text
Keywords: induced pluripotent stem cells; cardiomyocytes; maturation; metabolism induced pluripotent stem cells; cardiomyocytes; maturation; metabolism
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MDPI and ACS Style

Horikoshi, Y.; Yan, Y.; Terashvili, M.; Wells, C.; Horikoshi, H.; Fujita, S.; Bosnjak, Z.J.; Bai, X. Fatty Acid-Treated Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes Exhibit Adult Cardiomyocyte-Like Energy Metabolism Phenotypes. Cells 2019, 8, 1095. https://doi.org/10.3390/cells8091095

AMA Style

Horikoshi Y, Yan Y, Terashvili M, Wells C, Horikoshi H, Fujita S, Bosnjak ZJ, Bai X. Fatty Acid-Treated Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes Exhibit Adult Cardiomyocyte-Like Energy Metabolism Phenotypes. Cells. 2019; 8(9):1095. https://doi.org/10.3390/cells8091095

Chicago/Turabian Style

Horikoshi, Yuichi, Yasheng Yan, Maia Terashvili, Clive Wells, Hisako Horikoshi, Satoshi Fujita, Zeljko J. Bosnjak, and Xiaowen Bai. 2019. "Fatty Acid-Treated Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes Exhibit Adult Cardiomyocyte-Like Energy Metabolism Phenotypes" Cells 8, no. 9: 1095. https://doi.org/10.3390/cells8091095

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