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- Title
Enhancing Maturation and Translatability of Human Pluripotent Stem Cell-Derived Cardiomyocytes through a Novel Medium Containing Acetyl-CoA Carboxylase 2 Inhibitor.
- 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
- Abstract
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.
- Subjects
ACETYL-CoA carboxylase; DRUG discovery; CARDIAC hypertrophy; SMALL molecules; PREPROENDOTHELIN
- Publication
Cells (2073-4409), 2024, Vol 13, Issue 16, p1339
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells13161339