A roadmap for the characterization of energy metabolism in human cardiomyocytes derived from induced pluripotent stem cells

TY - JOUR

T1 - A roadmap for the characterization of energy metabolism in human cardiomyocytes derived from induced pluripotent stem cells

AU - Emanuelli, Giulia

AU - Zoccarato, Anna

AU - Reumiller, Christina M.

AU - Papadopoulos, Angelos

AU - Chong, Mei

AU - Rebs, Sabine

AU - Betteridge, Kai

AU - Beretta, Matteo

AU - Streckfuss-Bömeke, Katrin

AU - Shah, Ajay M.

N1 - Funding Information: This work was supported by the British Heart Foundation (RE/18/2/34213 and CH/1999001/11735; AMS); a Fondation Leducq Transatlantic Network of Excellence award (17CVD04; AMS); the Department of Health via a National Institute for Health Research (NIHR) Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London (IS-BRC-1215-20006; AMS); the Deutsche Forschungsgemeinschaft through the International Research Training Group Award (IRTG) 1816 (KSB, AMS); and the German Center for Cardiovascular Research (DZHK; KSB). GE was a Joint PhD student under IRTG 1816. We thank Roland Fleck and the Centre of Ultrastructural Imaging at King's College London for providing the equipment and expertise in electron microscopy. We thank Katarzyna Kmiotek-Wasylewska, Sharwari Verma, Sandra Georgi, and Johanna Heine for the support provided. Funding Information: This work was supported by the British Heart Foundation ( RE/18/2/34213 and CH/1999001/11735 ; AMS); a Fondation Leducq Transatlantic Network of Excellence award ( 17CVD04 ; AMS); the Department of Health via a National Institute for Health Research (NIHR) Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London ( IS-BRC-1215-20006 ; AMS); the Deutsche Forschungsgemeinschaft through the International Research Training Group Award (IRTG) 1816 (KSB, AMS); and the German Center for Cardiovascular Research (DZHK; KSB). GE was a Joint PhD student under IRTG 1816. We thank Roland Fleck and the Centre of Ultrastructural Imaging at King's College London for providing the equipment and expertise in electron microscopy. Publisher Copyright: © 2021 Elsevier Ltd

PY - 2022/3

Y1 - 2022/3

N2 - Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are an increasingly employed model in cardiac research and drug discovery. As cellular metabolism plays an integral role in determining phenotype, the characterization of the metabolic profile of hiPSC-CM during maturation is crucial for their translational application. In this study we employ a combination of methods including extracellular flux, 13C-glucose enrichment and targeted metabolomics to characterize the metabolic profile of hiPSC-CM during their maturation in culture from 6 weeks, up to 12 weeks. Results show a progressive remodeling of pathways involved in energy metabolism and substrate utilization along with an increase in sarcomere regularity. The oxidative capacity of hiPSC-CM and particularly their ability to utilize fatty acids increased with time. In parallel, relative glucose oxidation was reduced while glutamine oxidation was maintained at similar levels. There was also evidence of increased coupling of glycolysis to mitochondrial respiration, and away from glycolytic branch pathways at later stages of maturation. The rate of glycolysis as assessed by lactate production was maintained at both stages but with significant alterations in proximal glycolytic enzymes such as hexokinase and phosphofructokinase. We observed a progressive maturation of mitochondrial oxidative capacity at comparable levels of mitochondrial content between these time-points with enhancement of mitochondrial network structure. These results show that the metabolic profile of hiPSC-CM is progressively restructured, recapitulating aspects of early post-natal heart development. This would be particularly important to consider when employing these cell model in studies where metabolism plays an important role.

AB - Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are an increasingly employed model in cardiac research and drug discovery. As cellular metabolism plays an integral role in determining phenotype, the characterization of the metabolic profile of hiPSC-CM during maturation is crucial for their translational application. In this study we employ a combination of methods including extracellular flux, 13C-glucose enrichment and targeted metabolomics to characterize the metabolic profile of hiPSC-CM during their maturation in culture from 6 weeks, up to 12 weeks. Results show a progressive remodeling of pathways involved in energy metabolism and substrate utilization along with an increase in sarcomere regularity. The oxidative capacity of hiPSC-CM and particularly their ability to utilize fatty acids increased with time. In parallel, relative glucose oxidation was reduced while glutamine oxidation was maintained at similar levels. There was also evidence of increased coupling of glycolysis to mitochondrial respiration, and away from glycolytic branch pathways at later stages of maturation. The rate of glycolysis as assessed by lactate production was maintained at both stages but with significant alterations in proximal glycolytic enzymes such as hexokinase and phosphofructokinase. We observed a progressive maturation of mitochondrial oxidative capacity at comparable levels of mitochondrial content between these time-points with enhancement of mitochondrial network structure. These results show that the metabolic profile of hiPSC-CM is progressively restructured, recapitulating aspects of early post-natal heart development. This would be particularly important to consider when employing these cell model in studies where metabolism plays an important role.

KW - Cardiac cell models

KW - Energy metabolism

KW - iPSC-derived cardiomyocytes

KW - Metabolic maturation

KW - Metabolic shift

UR - http://www.scopus.com/inward/record.url?scp=85121275521&partnerID=8YFLogxK

U2 - 10.1016/j.yjmcc.2021.12.001

DO - 10.1016/j.yjmcc.2021.12.001

M3 - Article

AN - SCOPUS:85121275521

SN - 0022-2828

VL - 164

SP - 136

EP - 147

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

ER -