Metabolic substrate shift in human induced pluripotent stem cells during cardiac differentiation: Functional assessment using in vitro radionuclide uptake assay

Nose, Naoko; Werner, Rudolf A.; Ueda, Yuichiro; Günther, Katharina; Lapa, Constantin; Javadi, Mehrbod S.; Fukushima, Kazuhito; Edenhofer, Frank; Higuchi, Takahiro

doi:10.1016/j.ijcard.2018.06.089

Cited by 21 publications

(17 citation statements)

References 21 publications

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“…When hiPSCs exit pluripotency, they undergo metabolic remodeling so that energy production is converted to a mechanism that heavily relies on OxPhos and less on glycolysis (Moussaieff et al, 2015). The results of an in vitro tracer uptake study indicated a shift in the use of metabolic substrate from glucose to fatty acids after cardiac differentiation, which was similar to that observed in naturally isolated human cardiomyocytes (Nose et al, 2018).…”

Section: Introductionmentioning

confidence: 60%

Activation of AMPK Promotes Maturation of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Liang

Zhang

Zhou

et al. 2021

Front. Cell Dev. Biol.

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Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) (hiPSC-CMs) are a promising cell source for disease modeling, myocardial regeneration, and drug assessment. However, hiPSC-CMs have certain immature fetal CM-like properties that are different from the characteristics of adult CMs in several aspects, including cellular structure, mitochondrial function, and metabolism, thus limiting their applications. Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) is an energy-sensing protein kinase involved in the regulation of fatty acid oxidation and mitochondrial biogenesis in cardiomyocytes. This study investigated the effects of AMPK on the maturation of hiPSC-CMs. Activation of AMPK in hiPSC-CMs significantly increased the expression of CM-specific markers and resulted in a more mature myocardial structure compared to that in the control cells. We found that activation of AMPK improved mitochondrial oxidative phosphorylation (OxPhos) and the oxygen consumption rate (OCR). Additionally, our data demonstrated that activation of AMPK increased mitochondrial fusion to promote the maturation of mitochondrial structure and function. Overall, activation of AMPK is an effective approach to promote hiPSC-CMs maturation, which may enhance the utility of hiPSC-CMs in clinical applications.

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Section: Introductionmentioning

confidence: 60%

Activation of AMPK Promotes Maturation of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Liang

Zhang

Zhou

et al. 2021

Front. Cell Dev. Biol.

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“…PSC-CMs also demonstrate a decrease in 18 F-FDG uptake relative to 125 I-BMIPP (fatty acid analog) uptake at 2 weeks of cardiomyocyte differentiation that increases further to at least week 8 of differentiation, indicating that PSC-CMs undergo a metabolic switch from using glucose to fatty acids during differentiation [50]. Standard media used for culture of PSC-CMs in vitro often has supraphysiologic levels of glucose (DMEM 4.5 g/L = 25 mM, DMEM/F12 31.5 g/L = 17.5 mM, RPMI 2 g/L = 11.1 mM glucose versus physiologic levels of~5.5 mM).…”

Section: Glucosementioning

confidence: 99%

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

Garbern

Lee

2021

Stem Cell Res Ther

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Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.

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“…Energy production in hiPSC-cardiomyocytes results from glycolysis and oxidative phosphorylation of mainly lactate (Hattori et al, 2010; Lopaschuk and Jaswal, 2010; Rana et al, 2012; Ellen Kreipke et al, 2016), while the primary source of energy in healthy mature cardiomyocytes originates from mitochondrial aerobic metabolism, being approximately 90% derived from fatty acid oxidation into acetyl-CoA prior to integration in the citrate cycle (Harris and Das, 1991; Opie, 2004a). Recent work has demonstrated the possibility to enhance the metabolic maturity of hiPSC-cardiomyocytes through induction of fatty acid metabolism (Hu et al, 2018; Nose et al, 2018; Ramachandra et al, 2018) and with 3D microenvironments that can enable increased contractile work (Correia et al, 2018; Ulmer et al, 2018). Such strategies can improve the use of hiPSC-cardiomyocytes to evaluate drug effects that mechanistically depend on metabolism.…”

Section: Increasing the Contractile Physiological Relevance Of Hipsc-mentioning

confidence: 99%

Considerations for an In Vitro, Cell-Based Testing Platform for Detection of Drug-Induced Inotropic Effects in Early Drug Development. Part 2: Designing and Fabricating Microsystems for Assaying Cardiac Contractility With Physiological Relevance Using Human iPSC-Cardiomyocytes

et al. 2019

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Contractility of the myocardium engines the pumping function of the heart and is enabled by the collective contractile activity of its muscle cells: cardiomyocytes. The effects of drugs on the contractility of human cardiomyocytes in vitro can provide mechanistic insight that can support the prediction of clinical cardiac drug effects early in drug development. Cardiomyocytes differentiated from human-induced pluripotent stem cells have high potential for overcoming the current limitations of contractility assays because they attach easily to extracellular materials and last long in culture, while having human- and patient-specific properties. Under these conditions, contractility measurements can be non-destructive and minimally invasive, which allow assaying sub-chronic effects of drugs. For this purpose, the function of cardiomyocytes in vitro must reflect physiological settings, which is not observed in cultured cardiomyocytes derived from induced pluripotent stem cells because of the fetal-like properties of their contractile machinery. Primary cardiomyocytes or tissues of human origin fully represent physiological cellular properties, but are not easily available, do not last long in culture, and do not attach easily to force sensors or mechanical actuators. Microengineered cellular systems with a more mature contractile function have been developed in the last 5 years to overcome this limitation of stem cell–derived cardiomyocytes, while simultaneously measuring contractile endpoints with integrated force sensors/actuators and image-based techniques. Known effects of engineered microenvironments on the maturity of cardiomyocyte contractility have also been discovered in the development of these systems. Based on these discoveries, we review here design criteria of microengineered platforms of cardiomyocytes derived from pluripotent stem cells for measuring contractility with higher physiological relevance. These criteria involve the use of electromechanical, chemical and morphological cues, co-culture of different cell types, and three-dimensional cellular microenvironments. We further discuss the use and the current challenges for developing and improving these novel technologies for predicting clinical effects of drugs based on contractility measurements with cardiomyocytes differentiated from induced pluripotent stem cells. Future research should establish contexts of use in drug development for novel contractility assays with stem cell–derived cardiomyocytes.

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Metabolic substrate shift in human induced pluripotent stem cells during cardiac differentiation: Functional assessment using in vitro radionuclide uptake assay

Cited by 21 publications

References 21 publications

Activation of AMPK Promotes Maturation of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Activation of AMPK Promotes Maturation of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

Considerations for an In Vitro, Cell-Based Testing Platform for Detection of Drug-Induced Inotropic Effects in Early Drug Development. Part 2: Designing and Fabricating Microsystems for Assaying Cardiac Contractility With Physiological Relevance Using Human iPSC-Cardiomyocytes

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