Enhancing Maturation and Translatability of Human Pluripotent Stem Cell-Derived Cardiomyocytes through a Novel Medium Containing Acetyl-CoA Carboxylase 2 Inhibitor

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 16; p. 1339
• Main Authors: Correia, Cláudia, Christoffersson, Jonas, Tejedor, Sandra, El-Haou, Saïd, Matadamas-Guzman, Meztli, Nair, Syam, Dönnes, Pierre, Musa, Gentian, Rohman, Mattias, Sundqvist, Monika, Riddle, Rebecca B, Nugraha, Bramasta, Bellido, Ioritz Sorzabal, Johansson, Markus, Wang, Qing-Dong, Hidalgo, Alejandro, Jennbacken, Karin, Synnergren, Jane, Später, Daniela
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.08.2024; MDPI
• Subjects: ACACB protein; acetyl coenzyme A carboxylase; Acetyl-CoA Carboxylase; Acetyl-CoA Carboxylase - antagonists & inhibitors; Acetyl-CoA Carboxylase - metabolism; acetyl-CoA carboxylase 2 (ACC2); animal; Animals; Basic Medicine; Bioinformatics; Bioinformatik; Cardiac; cardiac hypertrophy; cardiac muscle cell; Cardiomyocytes; Cardiotoxicity; Cell culture; Cell Differentiation; Cell Differentiation - drug effects; Coronary artery disease; Culture Media; Culture Media - pharmacology; culture medium; cytology; Drug discovery; drug effect; Drug screening; Endothelin 1; enzyme inhibitor; Enzyme Inhibitors; Enzyme Inhibitors - pharmacology; Experiments; Fatty acids; Fetuses; Glucose; Heart cells; Heart diseases; human; human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) maturation; Humans; in vitro-to-in vivo correlation; Insulin; Ivabradine; Kinases; Maturation; Medicin och hälsovetenskap; Medicinska grundvetenskaper; Metabolism; Muscle contraction; Myocytes; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Oxidation; pharmacology; Phenotypes; Pluripotency; pluripotent stem cell; Pluripotent Stem Cells; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - drug effects; Pluripotent Stem Cells - metabolism; Stem cells; Structure-function relationships; translatable in vitro model; United Kingdom; Sweden; Germany; United States > US; Europe; acetyl-CoA carboxylase 2 (ACC2); translatable in vitro model; cardiac hypertrophy; human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) maturation; in vitro-to-in vivo correlation
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13161339

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) constitute an appealing tool for drug discovery, disease modeling, and cardiotoxicity screening. However, their physiological immaturity, resembling CMs in the late fetal stage, limits their utility. Herein, we have developed a novel, scalable cell culture medium designed to enhance the maturation of hPSC-CMs. This medium facilitates a metabolic shift towards fatty acid utilization and augments mitochondrial function by targeting Acetyl-CoA carboxylase 2 (ACC2) with a specific small molecule inhibitor. Our findings demonstrate that this maturation protocol significantly advances the metabolic, structural, molecular and functional maturity of hPSC-CMs at various stages of differentiation. Furthermore, it enables the creation of cardiac microtissues with superior structural integrity and contractile properties. Notably, hPSC-CMs cultured in this optimized maturation medium display increased accuracy in modeling a hypertrophic cardiac phenotype following acute endothelin-1 induction and show a strong correlation between in vitro and in vivo target engagement in drug screening efforts. This approach holds promise for improving the utility and translatability of hPSC-CMs in cardiac disease modeling and drug discovery.