Enhancing Maturation and Translatability of Human Pluripotent Stem Cell-Derived Cardiomyocytes through a Novel Medium Containing Acetyl-CoA Carboxylase 2 Inhibitor 2024 (English)In: Cells, E-ISSN 2073-4409, Vol. 13, no 16, article id 1339Article in journal (Refereed) Published

Abstract [en]

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. 

Place, publisher, year, edition, pages

MDPI, 2024. Vol. 13, no 16, article id 1339

Keywords [en]

acetyl-CoA carboxylase 2 (ACC2), cardiac hypertrophy, human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) maturation, in vitro-to-in vivo correlation, translatable in vitro model, Acetyl-CoA Carboxylase, Animals, Cell Differentiation, Culture Media, Enzyme Inhibitors, Humans, Myocytes, Cardiac, Pluripotent Stem Cells, ACACB protein, human, acetyl coenzyme A carboxylase, enzyme inhibitor, animal, cardiac muscle cell, culture medium, cytology, drug effect, human, metabolism, pharmacology, pluripotent stem cell

National Category

Biochemistry Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Research subject

Bioinformatics

Identifiers

URN: urn:nbn:se:his:diva-24484DOI: 10.3390/cells13161339ISI: 001305588500001PubMedID: 39195229Scopus ID: 2-s2.0-85202643852OAI: oai:DiVA.org:his-24484DiVA, id: diva2:1895266

Funder

Knut and Alice Wallenberg FoundationSwedish Research CouncilSwedish National Infrastructure for Computing (SNIC)Karolinska Institute

Note

CC BY 4.0 Deed

© 2024 by the authors.

Correspondence Address: C. Correia; Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43150, Sweden; email: claudia.correia@astrazeneca.com; D. Später; Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, 43150, Sweden; email: daniela.spaeter@astrazeneca.com

The authors acknowledge support from the National Genomics Infrastructure in Genomics Production Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, the Swedish Research Council, and the SNIC/Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. Further acknowledgment to the Single Cell Core Facility Flemingsberg campus (SICOF) at the Karolinska Institutet for sequencing support of the hiPSC C32 line. The authors also acknowledge Mario Soriano, from Príncipe Felipe Research Institute, for supporting TEM analyses; Ernst Wolvetang and Justin Copper-White from the University of Queensland for providing the hiPSC C32 line; Henrik Andersson and David Weisbrod, for support in using the FDSS/μCell system for calcium flux analysis and discussion of electrophysiology results; Angela Martinez Monleon for supporting RNA extraction; Hao Xu for supporting sarcomere structure analyses; Emil Hansson and Nelly Rahkonen from the Karolinska Institute for meaningful scientific discussions, input and support; Stefan Hallén for valuable discussions about the role of ACC inhibition in metabolism; Nina Krutrök for support with in vivo studies; Thomas Hochdörfer for supporting in vitro studies; Marcus Henricsson for supporting biomarker analysis; Patricia Rodrigues for performing isolation of adult mice CMs for seahorse experiments; Marina Leone for experimental support and discussions about CM maturation.

Available from: 2024-09-05 Created: 2024-09-05 Last updated: 2025-02-20Bibliographically approved

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