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

Emanuelli, Giulia; Zoccarato, Anna; Reumiller, Christina M; Papadopoulos, Angelos; Chong, Mei; Rebs, Sabine; Betteridge, Kai; Beretta, Matteo; Streckfuß‐Bömeke, Katrin; Shah, Ajay M.

doi:10.1016/j.yjmcc.2021.12.001

Cited by 16 publications

(16 citation statements)

References 55 publications

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“…Gene expression levels were reported in 18 out of 23 studies that examine metabolism in maturing iPSC-CMs. Expression levels of genes that regulate cardiac metabolism such as PDK4, CD36, PPARA , ATP5 , LPL , ACAT1 , DGAT1 and CPT1A/1B increase in iPSC-CMs when they are subjected to maturation strategies such as prolonged culture [ 4 , 13 , 18 ], 3D tissues [ 26 ] and fatty acid supplementation [ 14 , 21 , 24 , 35 , 52 , 70 , 93 , 95 ]. In addition, the expression of mitochondrial biogenesis-related genes including PPARGC1A and ESRRA was upregulated when iPSC-CMs were matured by prolonged culture [ 13 ] and fatty acid supplementation [ 70 ].…”

Section: Metabolic Characteristics Of Maturing Ipsc-cmsmentioning

confidence: 99%

Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling

et al. 2022

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Background Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have emerged as a powerful tool for disease modeling, though their immature nature currently limits translation into clinical practice. Maturation strategies increasingly pay attention to cardiac metabolism because of its pivotal role in cardiomyocyte development and function. Moreover, aberrances in cardiac metabolism are central to the pathogenesis of cardiac disease. Thus, proper modeling of human cardiac disease warrants careful characterization of the metabolic properties of iPSC-CMs. Methods Here, we examined the effect of maturation protocols on healthy iPSC-CMs applied in 23 studies and compared fold changes in functional metabolic characteristics to assess the level of maturation. In addition, pathological metabolic remodeling was assessed in 13 iPSC-CM studies that focus on hypertrophic cardiomyopathy (HCM), which is characterized by abnormalities in metabolism. Results Matured iPSC-CMs were characterized by mitochondrial maturation, increased oxidative capacity and enhanced fatty acid use for energy production. HCM iPSC-CMs presented varying degrees of metabolic remodeling ranging from compensatory to energy depletion stages, likely due to the different types of mutations and clinical phenotypes modeled. HCM further displayed early onset hypertrophy, independent of the type of mutation or disease stage. Conclusions Maturation strategies improve the metabolic characteristics of iPSC-CMs, but not to the level of the adult heart. Therefore, a combination of maturation strategies might prove to be more effective. Due to early onset hypertrophy, HCM iPSC-CMs may be less suitable to detect early disease modifiers in HCM and might prove more useful to examine the effects of gene editing and new drugs in advanced disease stages. With this review, we provide an overview of the assays used for characterization of cardiac metabolism in iPSC-CMs and advise on which metabolic assays to include in future maturation and disease modeling studies.

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Section: Metabolic Characteristics Of Maturing Ipsc-cmsmentioning

confidence: 99%

Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling

et al. 2022

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“…Secondly, compared with isolated adult cardiomyocytes from the human myocardium, iPSC CM resemble an immature/neonatal status of cardiac cells. To overcome the limitation of inherently immature iPSC-derivatives in the study of late-onset diseases, we used a prolonged culture of at least 60–90 d to foster maturation, as shown in our previous study for the metabolic profile of iPSC-CM [ 10 ]. Nevertheless, the iPSC CM still does not resemble an adult phenotype.…”

Section: Limitationsmentioning

confidence: 99%

Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients

et al. 2022

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Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20+ B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms. In cellular studies, ACT-iPSC CM were persistently more susceptible to DOX toxicity including augmented disorganized myofilament structure, changed mitochondrial shape, and increased apoptotic events. Consistently, ACT-iPSC CM and cardiac fibroblasts isolated from fibrotic human ACT myocardium exhibited higher DOX-dependent reactive oxygen species. In functional studies, Ca2+ transient amplitude of ACT-iPSC CM was reduced compared to control cells, and diastolic sarcoplasmic reticulum Ca2+ leak was DOX-dependently increased. This could be explained by overactive CaMKIIδ in ACT CM. Together with DOX-dependent augmented proarrhythmic cellular triggers and prolonged action potentials in ACT CM, this suggests a cellular link to arrhythmogenic events and contractile dysfunction especially found in ACT engineered human myocardium. CamKIIδ inhibition prevented proarrhythmic triggers in ACT. In contrast, control CM upregulated SERCA2a expression in a DOX-dependent manner, possibly to avoid heart failure conditions. In conclusion, we developed the first human patient-specific stem cell model of DOX-induced cardiac dysfunction from patients with B-cell lymphoma. Our results suggest that DOX-induced stress resulted in arrhythmogenic events associated with contractile dysfunction and finally in heart failure after persistent stress activation in ACT patients.

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“…The above studies on in vitro hESC-CMs metabolic maturation well corroborated with in vivo discoveries regarding fetal cardiac metabolic changes during terminal maturation, leading to a more comprehensive understanding of fetal cardiac metabolic remodeling. Emanuelli et al (2021) very recently characterized the metabolic profile of human cardiomyocytes induced from pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) during their maturation from 6 to 12 weeks in culture. hiPSC-CMs exhibited ongoing structural maturation but no significant change in the glycolytic reserve, glucose uptake, or main glycolytic enzymes over 6 weeks of prolonged culture.…”

Section: Metabolic Remodeling In Heart Developmentmentioning

confidence: 99%

New Insights Into Energy Substrate Utilization and Metabolic Remodeling in Cardiac Physiological Adaption

Shi

Qiu

2022

Front. Physiol.

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Cardiac function highly relies on sufficient energy supply. Perturbations in myocardial energy metabolism play a causative role in cardiac pathogenesis. Accumulating evidence has suggested that modifications of cardiac metabolism are also an essential part of the adaptive responses to various physiological conditions in the heart to meet specific energy needs. The review highlighted some new studies on basic myocardial energy substrate metabolism and updated recent findings regarding cardiac metabolic remodeling and their associated mechanisms under physiological conditions, including exercise and cardiac development. Studying basic metabolic profiles in the heart in these conditions can contribute to understanding the significance of metabolic regulation in the heart during physiological adaption and gaining further insights into the maladaptive metabolic changes associated with cardiac pathogenesis, thus opening up new avenues to exploring novel therapeutic strategies in cardiac diseases.

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

Cited by 16 publications

References 55 publications

Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling

Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling

Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients

New Insights Into Energy Substrate Utilization and Metabolic Remodeling in Cardiac Physiological Adaption

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