Distinct carbon sources affect structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells

Correia, Catarina; Koshkin, Alexey; Duarte, Patrícia; Hu, Dongjian; Teixeira, Augusto; Domian, Ibrahim J.; Serra, Margarida; Alves, Paula M.

doi:10.1038/s41598-017-08713-4

Cited by 181 publications

(184 citation statements)

References 70 publications

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“…For example immature hPSC-derived CMs showed a preference for oxidation of β-hydroxybutryrate when supplied in our culture conditions, consistent with the physiology of the heart, and should be explored as potential maturation agent (Nagao et al, 2016, Gormsen et al, 2017. Indeed, galactose and fatty acid supplementation has already been utilized to enhance and demonstrates the utility of these approaches (Correia et al, 2017). Our results further demonstrate that environmental nutrient conditions can drive influence maturation of hPSC-derived CMs and promote improved metabolic phenotypes in vitro.…”

Section: Discussionsupporting

confidence: 70%

“…However recent work has definitively demonstrated that activating mitochondrial function through galactose supplementation induces a more mature CM metabolism (i.e. fatty acid oxidation) and better function in hPSC-derived CMs (Correia et al, 2017). The role of mitochondrial substrate switching during CM differentiation and the role of fatty acid metabolism during maturation is underexplored.…”

Section: Introductionmentioning

confidence: 99%

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Lipid availability influences the metabolic maturation of human pluripotent stem cell-derived cardiomyocytes

Zhang¹,

Badur²,

Spiering

et al. 2020

Preprint

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ObjectivesPluripotent stem cell-derived cardiomyocytes are phenotypically immature, which limits their utility in downstream applications. Metabolism is dramatically reprogramed during cardiac maturation in vivo and presents a potential avenue to drive in vitro maturation. We aimed to identify and address metabolic bottlenecks in the generation of human pluripotent stem cell (hPSC)-derived cardiomyocytes.Methods hPSCs were differentiated into cardiomyocytes using an established, chemically-defined differentiation protocol. We applied 13C metabolic flux analysis (MFA) and targeted transcriptomics to characterize cardiomyocyte metabolism in during differentiation in the presence or absence of exogenous lipids. ResultshPSC-derived cardiomyocytes induced some cardiometabolic pathways (i.e. ketone body and branched-chain amino acid oxidation) but failed to effectively activate fatty acid oxidation. MFA studies indicated that lipid availability in cultures became limited during differentiation, suggesting potential issues with nutrient availability. Exogenous supplementation of lipids improved cardiomyocyte morphology, mitochondrial function, and promoted increased fatty acid oxidation in hPSC-derivatives. ConclusionhPSC-derived cardiomyocytes are dependent upon exogenous sources of lipids for metabolic maturation. Proper supplementation removes a potential roadblock in the generation of metabolically mature cardiomyocytes. These studies further highlight the importance of considering and exploiting metabolic phenotypes in the in vitro production and utilization of functional hPSC-derivatives.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Lipid availability influences the metabolic maturation of human pluripotent stem cell-derived cardiomyocytes

Zhang¹,

Badur²,

Spiering

et al. 2020

Preprint

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“…To investigate whether hiPSC-CMs could be shifted towards more adult-like morphology and behavior, a combinatorial approach was employed. First, instead of using media where glucose is the main energy source (GLUC) our cells were cultured in media where glucose was substituted with a combination of galactose, oleic acid, and palmitic acid (maturity medium, MM) based on previous reports of similar methods that improve cellular morphology, contractility, ATP content, and metabolic behavior 7,8 . Although both GLUC and MM each contain the B-27™ supplement, which contains several fatty acids, total fatty acid content in MM is ~150µmol versus ~144nM in B-27™-supplemented RPMI 9 .…”

Section: Maturation Methods Improve Both Hipsc-cm and Sarcomeric Morpmentioning

confidence: 99%

Maturation of human induced pluripotent stem cell-derived cardiomyocytes for modeling hypertrophic cardiomyopathy

Knight

Cao

Lin

et al. 2020

Preprint

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Rationale: Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are a powerful platform for biomedical research. However, they are immature, which is a barrier to modeling adult-onset cardiovascular disease. Objective: We sought to develop a simple method which could drive cultured hiPSC-CMs towards maturity across a number of phenotypes. Methods and results: Cells were cultured in fatty acid-based media and plated on micropatterned surfaces to promote alignment and elongation.These cells display many characteristics of adult human cardiomyocytes, including elongated cell morphology, enhanced maturity of sarcomeric structures, metabolic behavior, and increased myofibril contractile force. Most notably, hiPSC-CMs cultured under optimal maturity-inducing conditions recapitulate the pathological hypertrophy caused by either a pro-hypertrophic agent or genetic mutations. Conclusions: The more mature hiPSC-CMs produced by the methods described here will serve as a useful in vitro platform for characterizing cardiovascular disease. Abbreviations: CL: Cardiolipin CPT: Carnitine palmitoyltransferase GLUC: Glucose cells: hiPSC-CMs cultured in glucose-based media hiPSC-CMs: Human pluripotent stem cell-derived cardiomyocytes MM: Maturation medium: hiPSC-CMs cultured in fatty acid-based media MPAT: Maturation medium/patterned cells: hiPSC-CMs cultured on patterned surfaces in fatty acid-based media MYH: myosin heavy chain

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“…Intriguingly, several studies have hinted at significant co-regulation of maturation processes. As an example, fatty acid treatment of PSC-CMs not only results in expected improvements in PSC-CM metabolic maturation, but also leads to improvements in sarcomeric gene expression and structure, calcium handling and cell cycle inhibition (Correia et al 2017;Mills et al 2017). This in turn suggests potential regulation of structural, functional and cell cycle maturation through a metabolic mechanism.…”

Section: Regulation Of Coordinated Maturation Processesmentioning

confidence: 99%

Regulation of cardiomyocyte maturation during critical perinatal window

Kannan

Kwon

2019

The Journal of Physiology

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A primary limitation in the use of pluripotent stem cell-derived cardiomyocytes (PSC-CMs) for both patient health and scientific investigation is the failure of these cells to achieve full functional maturity. In vivo, cardiomyocytes undergo numerous adaptive structural, functional and metabolic changes during maturation. By contrast, PSC-CMs fail to fully undergo these developmental processes, instead remaining arrested at an embryonic stage of maturation. There is thus a significant need to understand the biological processes underlying proper CM maturation in vivo. Here, we discuss what is known regarding the initiation and coordination of CM maturation. We postulate that there is a critical perinatal window, ranging from embryonic day 18.5 to postnatal day 14 in mice, in which the maturation process is exquisitely sensitive to perturbation. While the initiation mechanisms of this process are unknown, it is increasingly clear that maturation proceeds through interconnected regulatory circuits that feed into one another to coordinate concomitant structural, functional and metabolic CM maturation. We highlight PGC1α, SRF and the MEF2 family as transcription factors that may potentially mediate this cross-talk. We lastly discuss several emerging technologies that will facilitate future studies into the mechanisms of CM maturation. Further study will not only produce a better understanding of its key processes, but provide practical insights into developing a robust strategy to produce mature PSC-CMs. Abstract figure legendHere, we postulate that there is a critical window, ranging from embryonic day 18.5 to postnatal day 14 in mice, in which interconnected regulatory circuits enable coordinated, concomitant structural, functional and metabolic cardiomyocyte maturation.

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Distinct carbon sources affect structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells

Cited by 181 publications

References 70 publications

Lipid availability influences the metabolic maturation of human pluripotent stem cell-derived cardiomyocytes

Lipid availability influences the metabolic maturation of human pluripotent stem cell-derived cardiomyocytes

Maturation of human induced pluripotent stem cell-derived cardiomyocytes for modeling hypertrophic cardiomyopathy

Regulation of cardiomyocyte maturation during critical perinatal window

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