Functional and developmental properties of human embryonic stem cells–derived cardiomyocytes

Binah, Ofer; Dolnikov, Katya; Sadan, Oshra; Shilkrut, Mark; Zeevi‐Levin, Naama; Amit, Michal; Danon, Asaf; Itskovitz‐Eldor, Joseph

doi:10.1016/j.jelectrocard.2007.05.035

Cited by 73 publications

(69 citation statements)

References 15 publications

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“…This may be because mature cardiomyocytes rely on internal calcium stores for contraction whereas stem cellderived cardiomyocytes depend more on external calcium (Dolnikov et al, 2006) as they have underdeveloped SR capacity and t-tubule systems (Satin et al, 2004;Binah et al, 2007;Sedan et al, 2008). They therefore have immature calcium handling within the cell.…”

Section: Permission)mentioning

confidence: 99%

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

Khan

Lyon

Harding

2013

British J Pharmacology

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The current drug screening models are deficient, particularly in detecting cardiac side effects. Human stem cell-derived cardiomyocytes could aid both early cardiotoxicity detection and novel drug discovery. Work over the last decade has generated human embryonic stem cells as potentially accurate sources of human cardiomyocytes, but ethical constraints and poor efficacy in establishing cell lines limit their use. Induced pluripotent stem cells do not require the use of human embryos and have the added advantage of producing patient-specific cardiomyocytes, allowing both generic and disease-and patient-specific pharmacological screening, as well as drug development through disease modelling. A critical question is whether sufficient standards have been achieved in the reliable and reproducible generation of 'adult-like' cardiomyocytes from human fibroblast tissue to progress from validation to safe use in practice and drug discovery. This review will highlight the need for a new experimental system, assess the validity of human induced pluripotent stem cell-derived cardiomyocytes and explore what the future may hold for their use in pharmacology. LINKED ARTICLESThis article is part of a themed section on Regenerative Medicine and Pharmacology: A Look to the Future. To view the other articles in this section visit http://dx

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Section: Permission)mentioning

confidence: 99%

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

Khan

Lyon

Harding

2013

British J Pharmacology

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“…Pluripotent stem cell-derived cardiomyocytes (PSC-CMs), including human embryonic stem cell (hESC)-derived-and human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs), offer a number of advantages for cell-based cardiac repair, but most in vivo studies as of yet have shown only partial or transient restoration of contractile function [5][6][7][8]. One potential explanation is the underdeveloped contractile properties of PSC-CMs, which lack the robust contractile machinery found in mature adult CMs and instead resemble primitive CMs [9][10][11][12][13][14]. Even if PSC-CMs successfully engraft in the infarcted heart, it seems unlikely that in their current form, they possess the ability to replace the forcegenerating capacity of the mature myocardium lost during the initial insult.…”

Section: Introductionmentioning

confidence: 99%

Structural and Functional Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells

Lundy

Zhu

Regnier

et al. 2013

Stem Cells and Development

637

696

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Despite preclinical studies demonstrating the functional benefit of transplanting human pluripotent stem cellderived cardiomyocytes (PSC-CMs) into damaged myocardium, the ability of these immature cells to adopt a more adult-like cardiomyocyte (CM) phenotype remains uncertain. To address this issue, we tested the hypothesis that prolonged in vitro culture of human embryonic stem cell (hESC)-and human induced pluripotent stem cell (hiPSC)-derived CMs would result in the maturation of their structural and contractile properties to a more adult-like phenotype. Compared to their early-stage counterparts (PSC-CMs after 20-40 days of in vitro differentiation and culture), late-stage hESC-CMs and hiPSC-CMs (80-120 days) showed dramatic differences in morphology, including increased cell size and anisotropy, greater myofibril density and alignment, sarcomeres visible by bright-field microscopy, and a 10-fold increase in the fraction of multinucleated CMs. Ultrastructural analysis confirmed improvements in the myofibrillar density, alignment, and morphology. We measured the contractile performance of late-stage hESC-CMs and hiPSC-CMs and noted a doubling in shortening magnitude with slowed contraction kinetics compared to the early-stage cells. We then examined changes in the calciumhandling properties of these matured CMs and found an increase in calcium release and reuptake rates with no change in the maximum amplitude. Finally, we performed electrophysiological assessments in hESC-CMs and found that late-stage myocytes have hyperpolarized maximum diastolic potentials, increased action potential amplitudes, and faster upstroke velocities. To correlate these functional changes with gene expression, we performed qPCR and found a robust induction of the key cardiac structural markers, including b-myosin heavy chain and connexin-43, in late-stage hESC-CMs and hiPSC-CMs. These findings suggest that PSC-CMs are capable of slowly maturing to more closely resemble the phenotype of adult CMs and may eventually possess the potential to regenerate the lost myocardium with robust de novo force-producing tissue.

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“…The atrial myocyte fate was specified by exogenous retinoid acid treatment and Conversely, a previous study on mouse ESCs represented that the specification of ventricular CM is enhanced by retinoid acid application [293]. This result showed differences between the differentiation culture systems (i.e., mouse ESCs vs human ESCs vs iPSCs), method of differentiation (i.e., EB vs monolayer method), and timing of application could affect on cardiac specification.…”

Section: Differentiation Of Human Epc-ipsc Into Cardiac Chamber-specimentioning

confidence: 82%

“…Finally the functional profiling has demonstrated that the Ca+ handling in PSC-CM shows an immature sarcoplasmic reticulum capacity (SR) to store and release calcium ions. Thus, calcium ions enter the cells through the sarcolemma instead of being released by the SR and, ultimately result in slower of excitation-contraction coupling than adult CM [293][294][295]. Early stages of iPSC-CM demonstrate a proliferation rate similar to embryonic or fetal cardiomyocytes which is markedly decreased from the pluripotent state [296][297].…”

Section: Characterization Of Ipscs Derived Cardiomyocytesmentioning

confidence: 99%

Differentiation of Human Atrial Myocytes From Endothelial Progenitor Cell-Derived Induced Pluripotent Stem Cells

Jambi¹,

Ye²,

Gollob³

et al. 2013

Canadian Journal of Cardiology

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Functional and developmental properties of human embryonic stem cells–derived cardiomyocytes

Cited by 73 publications

References 15 publications

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

The case for induced pluripotent stem cell‐derived cardiomyocytes in pharmacological screening

Structural and Functional Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells

Differentiation of Human Atrial Myocytes From Endothelial Progenitor Cell-Derived Induced Pluripotent Stem Cells

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