Concise Review: Measuring Physiological Responses of Human Pluripotent Stem Cell Derived Cardiomyocytes to Drugs and Disease

Meer, Berend J. van; Tertoolen, Leon G.J.; Mummery, Christine L.

doi:10.1002/stem.2403

Cited by 67 publications

(56 citation statements)

References 74 publications

(74 reference statements)

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“…Here, we determined small molecule absorption by PDMS-coated culture wells versus standard culture plastic for four drugs that affect the heart, our primary research area [20], [21] for which there is interest in knowing their toxic threshold: verapamil, bepridil, Bay K 8644 and nifedipine. Toxic thresholds can only be determined accurately if the compound availability to cells is known.…”

Section: Introductionmentioning

confidence: 99%

Small molecule absorption by PDMS in the context of drug response bioassays

Meer

Vries

Firth

et al. 2017

Biochemical and Biophysical Research Communications

346

279

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The polymer polydimethylsiloxane (PDMS) is widely used to build microfluidic devices compatible with cell culture. Whilst convenient in manufacture, PDMS has the disadvantage that it can absorb small molecules such as drugs. In microfluidic devices like “Organs-on-Chip”, designed to examine cell behavior and test the effects of drugs, this might impact drug bioavailability. Here we developed an assay to compare the absorption of a test set of four cardiac drugs by PDMS based on measuring the residual non-absorbed compound by High Pressure Liquid Chromatography (HPLC). We showed that absorption was variable and time dependent and not determined exclusively by hydrophobicity as claimed previously. We demonstrated that two commercially available lipophilic coatings and the presence of cells affected absorption. The use of lipophilic coatings may be useful in preventing small molecule absorption by PDMS.

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Section: Introductionmentioning

confidence: 99%

Small molecule absorption by PDMS in the context of drug response bioassays

Meer

Vries

Firth

et al. 2017

Biochemical and Biophysical Research Communications

346

279

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“…14 Mechanical output has also been assayed with engineered multicellular systems composed of hiPSC-CMs or co-cultured with other cell types. 15 Induced intracellular alignment of myofibrils is central for accelerating the contractile maturity of hiPSC-CMs. 16 Myofibrils are easier to image in single cell systems, allowing the assessment of these structures in live hiPSC-CMs.…”

Section: Introductionmentioning

confidence: 99%

Multi-Imaging Method to Assay the Contractile Mechanical Output of Micropatterned Human iPSC-Derived Cardiac Myocytes

Ribeiro

Schwab

Mandegar

et al. 2017

Circulation Research

117

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Rationale During each beat, cardiac myocytes generate the mechanical output necessary for heart function through contractile mechanisms that involve shortening of sarcomeres along myofibrils. Human induced pluripotent stem cells can be differentiated into cardiac myocytes that model cardiac contractile mechanical output more robustly when micropatterned into physiological shapes. Quantifying the mechanical output of these cells enables us to assay cardiac activity in a dish. Objective We sought to develop a computational platform that integrates analytical approaches to quantify the mechanical output of single micropatterned cardiac myocytes from microscopy videos. Methods and Results We micropatterned single cardiac myocytes differentiated from human induced pluripotent stem cells on deformable polyacrylamide substrates containing fluorescent microbeads. We acquired videos of single beating cells, of microbead displacement during contractions, and of fluorescently labeled myofibrils. These videos were independently analyzed to obtain parameters that capture the mechanical output of the imaged single cells. We also developed novel methods to quantify sarcomere length from videos of moving myofibrils and to analyze loss of synchronicity of beating in cells with contractile defects. We tested this computational platform by detecting variations in mechanical output induced by drugs and in cells expressing low levels of myosin binding protein C. Conclusions Our method can measure cardiac function in cardiac myocytes differentiated from induced pluripotent stem cells and determine contractile parameters that can be used to elucidate the mechanisms that underlie variations in cardiac myocyte function. This platform will be amenable to future studies of the effects of mutations and drugs on cardiac function.

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“…The successful generation of cardiac disease models with hiPSC-CMs relies on their ability to recapitulate key aspects of CM biology, including their molecular, cellular and physiological properties, and on the scientist' tools and ability to record and capture these specific features and changes upon pathological or cardiotoxic conditions. For this, appropriate and sensitive read-out assays have been developed [13] and techniques are being continuously improved [22].…”

Section: Pathological Phenotypes and New Mechanistic Insightsmentioning

confidence: 99%

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

Bellin

Mummery

2016

FEBS Letters

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Induced pluripotent stem cells (iPSCs) were first generated 10 years ago. Their ability to differentiate into any somatic cell type of the body including cardiomyocytes has already made them a valuable resource for modelling cardiac disease and drug screening. Initially human iPSCs were used mostly to model known disease phenotypes; more recently, and despite a number of recognised shortcomings, they have proven valuable in providing fundamental insights into the mechanisms of inherited heart disease with unknown genetic cause using surprisingly small cohorts. In this review, we summarise the progress made with human iPSCs as cardiac disease models with special focus on the latest mechanistic insights and related challenges. Furthermore, we suggest emerging solutions that will likely move the field forward.

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Concise Review: Measuring Physiological Responses of Human Pluripotent Stem Cell Derived Cardiomyocytes to Drugs and Disease

Cited by 67 publications

References 74 publications

Small molecule absorption by PDMS in the context of drug response bioassays

Small molecule absorption by PDMS in the context of drug response bioassays

Multi-Imaging Method to Assay the Contractile Mechanical Output of Micropatterned Human iPSC-Derived Cardiac Myocytes

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

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