Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitro – Correlation between contraction force and electrophysiology

Ribeiro, Marcelo C.; Tertoolen, Leon G.J.; Guadix, Juan Antonio; Bellin, Milena; Kosmidis, Georgios; D’Aniello, Cristina; Monshouwer-Kloots, Jantine; Goumans, Marie–José; Wang, Yuli; Feinberg, Adam W.; Mummery, Christine L.; Passier, Robert

doi:10.1016/j.biomaterials.2015.01.067

Cited by 190 publications

(201 citation statements)

References 56 publications

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“…4C) in let-7 OE CMs. The increase in APD90 and APD50/90, as well as increased expression of CACNA1C, has been shown to occur during cardiac maturation (42,43). These data together demonstrate not only that let-7 OE results in morphological and molecular changes indicative of maturation but also that functionally relevant parameters, such as APD, contraction, and beat frequency, are appropriately regulated.…”

Section: Let-7 Family Required and Sufficient For Maturation Of Hesc-cmmentioning

confidence: 49%

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Kuppusamy

Jones²,

Sperber

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

233

218

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In metazoans, transition from fetal to adult heart is accompanied by a switch in energy metabolism-glycolysis to fatty acid oxidation. The molecular factors regulating this metabolic switch remain largely unexplored. We first demonstrate that the molecular signatures in 1-year (y) matured human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are similar to those seen in in vivo-derived mature cardiac tissues, thus making them an excellent model to study human cardiac maturation. We further show that let-7 is the most highly up-regulated microRNA (miRNA) family during in vitro human cardiac maturation. Gain-and loss-of-function analyses of let-7g in hESC-CMs demonstrate it is both required and sufficient for maturation, but not for early differentiation of CMs. Overexpression of let-7 family members in hESC-CMs enhances cell size, sarcomere length, force of contraction, and respiratory capacity. Interestingly, large-scale expression data, target analysis, and metabolic flux assays suggest this let-7-driven CM maturation could be a result of down-regulation of the phosphoinositide 3 kinase (PI3K)/AKT protein kinase/insulin pathway and an up-regulation of fatty acid metabolism. These results indicate let-7 is an important mediator in augmenting metabolic energetics in maturing CMs. Promoting maturation of hESC-CMs with let-7 overexpression will be highly significant for basic and applied research.everal coronary heart diseases (CHDs) are characterized by cardiac dysfunctions predominantly manifested during cardiac maturation (1, 2). Dramatic changes in energy metabolism occur during this postnatal cardiac maturation (3). At early embryonic development, glycolysis is a major source of energy for cardiomyocytes (CMs) (4, 5). However, as the cardiomyocytes mature, mitochondrial oxidative metabolism increases with fatty acid oxidation, providing 90% of the heart's energy demands (6-8). This switch in cardiac metabolism has been shown to have important implications during in vivo cardiac maturation (9). In contrast to the relatively advanced knowledge of the genetic network that contributes to heart development during embryogenesis (10, 11), molecular factors that regulate peri-and postnatal cardiac maturation, particularly in relation to the metabolic switch, remain largely unclear. So far, studies to understand the transition of the glycolysisdependent fetal heart to oxidative metabolism in the adult heart have been mostly related to the peroxisome proliferatoractivated receptor (PPAR)/estrogen-related receptor/PPARγ coactivator-1α circuit (7,8,12). However, it is currently unknown what other factors act upstream or in synergy with this pathway in controlling cardiac energetics.miRNAs have emerged as key factors in controlling the complex regulatory network in a developing heart (13). Genetic studies that enrich or deplete miRNAs in specific cardiac tissue types and large-scale gene expression studies have demonstrated that they achieve such complex control at the level of cardiac gene expression (14-16). We sou...

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Section: Let-7 Family Required and Sufficient For Maturation Of Hesc-cmmentioning

confidence: 49%

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Kuppusamy

Jones²,

Sperber

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

233

218

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“…Ca 2 + ‐handling also affects cell contractility, which can also be measured, as recent examples with sophisticated optical mapping systems show (Herron et al , 2012; Hayakawa et al , 2014; Maddah et al , 2015). The combination of engineering and biology has allowed the precise quantification of contractile force in hPSC‐CMs (Ribeiro et al , 2015a), although it has been demonstrated that substrate stiffness plays a major role in the quantification of absolute force values (Feinberg et al , 2012; Ribeiro et al , 2015b). More recently, integrated technologies capable of simultaneously quantifying multiple parameters are being implemented with the view to providing reliable, high‐throughput tools for early preclinical stages of drug development (Hochbaum et al , 2014; Kijlstra et al , 2015; Rast et al , 2015; Song et al , 2015; Dempsey et al , 2016; Klimas et al , 2016).…”

Section: Assays and Readoutsmentioning

confidence: 99%

“…Typical fetal features that they display include automaticity of beating, depolarized diastolic V m , low ion channel expression, delayed excitation‐contraction coupling and low contractile force (Veerman et al , 2015). Defined culture conditions (Burridge et al , 2014; Ribeiro et al , 2015a, 2015b) can be used to improve the maturation of hPSC‐CMs to reveal hidden disease phenotypes (Birket et al , 2015) or to drive differentiation to chamber‐specific cell populations (Devalla et al , 2015), and drug testing might benefit from their standardization. Exogenous stimuli, such as adjusted pacing frequency (Chan et al , 2013), 3D‐microenvironments (Zhao et al , 1999; Nunes et al , 2013; Hirt et al , 2014; Eder et al , 2016) and heterotypic cell co‐culture (Robertson et al , 2013) may all contribute to cell maturation, increasing the expression of ion channels and improving functional properties.…”

Section: Limitations In Applicability Of Hipsc‐cm To Large‐scale Drugmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

Self Cite

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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“…Although the electrophysiological recording for two-dimensional (2D) tissue has made significant contributions to biological researches, it has certain intrinsic limitations. Thus, several groups have proposed the development of three-dimensional (3D) in vitro tissue cultures for electrophysiological recordings [32][33][34]. Compared to 2D tissue for electrophysiological recording, the 3D tissue provides electrophysiological activities that more closely mimics the microenvironment observed in native tissues.…”

Section: D Tissue Electrophysiological Recordingmentioning

confidence: 99%

Gustatoty Epithelium-Based Taste Sensors

Zhang

Liu

2015

Bioinspired Smell and Taste Sensors

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Functional maturation of human pluripotent stem cell derived cardiomyocytes in vitro – Correlation between contraction force and electrophysiology

Cited by 190 publications

References 56 publications

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Gustatoty Epithelium-Based Taste Sensors

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