Applications

Discovery

Powerful New Strategies for Drug Discovery

Analysis of Phase II drug failures (Arrowsmith 2011, Arrowsmith and Miller 2013) identifies lack of efficacy as the most frequent cause of attrition, suggesting that existing in vitro and in vivo disease models are not well-translated to human disease. Efficacy obstacles are especially problematic for clinical targets, such as the central nervous system (CNS), with notoriously unpredictive animal models. Together, CDI’s iCell® and MyCell® Products enable powerful new strategies for overcoming these hurdles:

Contact us to learn how CDI’s iPS cell platform gives scientists a more in-depth biological understanding of drug targets and improved target validation approaches.

Advanced Cardiomyocyte Cell Culture

Advanced cell culture techniques including 3D spheroids, micropatterned co-culture, bioengineered and flow-based systems, and bioprinting offer the potential to better mimic in vivo tissue structure and function.

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Advanced Cardiomyocyte Cell Culture

Discovery, Regenerative Medicine, Toxicity

Advanced cell culture techniques including 3D spheroids, micropatterned co-culture, bioengineered and flow-based systems, and bioprinting offer the potential to better mimic in vivo tissue structure and function. CDI’s cardiomyocytes are amenable to these culture techniques as pure cell populations or in co-culture with other cell types, such as CDI’s iCell Endothelial Cells.

  1. Carlson C, Einhorn S, et al. (2013) Applications Development at CDI: Improving Workflows, Pushing Biology, and Enabling Screening. Poster Presentation, Cellular Dynamics User Group Meeting.
  2. Rao C, Prodromakis T, et al. (2013)  The Effect of Microgrooved Culture Substrates on Calcium Cycling of Cardiac Myocytes Derived from Human Induced Pluripotent Stem Cells. Biomaterials 34(10):2399-411.
  3. iCell Cardiomyocytes – iCell Endothelial Cells Co-culture. Contact Technical Support for more information.

Genetic Manipulation of Cardiomyocytes

The ability to interrogate and monitor gene expression is critical to understanding biological pathways that underlie normal and pathogenic cellular function.

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Genetic Manipulation of Cardiomyocytes

Discovery, Regenerative Medicine, Toxicity

The ability to interrogate and monitor gene expression is critical to understanding biological pathways that underlie normal and pathogenic cellular function. CDI’s cardiomyocytes are amenable to various genetic manipulation techniques including transfection, transduction, siRNA, and reporter vector expression.

Transfection and Transduction:

  1. iCell Products: Applying Transfection Technologies to Create Novel Screening Models. Cellular Dynamics Application Note.
  2. Robers M and Jarecki B. (2014) Efficiently Build Relevant In Vitro Models Using Human Stem Cell-derived Tissue Cells, High Performance Transfection and Novel Multiplexed Reporter Techniques. Promega/Cellular Dynamics Webinar.
  3. Anson B. (2015) Building Richer Assays: iPSC-derived Tissue Cells Are a Powerful Addition to the Biologist’s Tool Box. GEN 35(2).
  4. Traister A, Li M, et al. (2014) Integrin-linked Kinase Mediates Force Transduction in Cardiomyocytes by Modulating SERCA2a/PLN Function. Nature Comm 5:4533.
  5. Fine M, Lu F, et al. (2013) Human Induced Pluripotent Stem Cell-derived Cardiomyocytes for Studies of Cardiac Ion Transporters. Am J Physiol Cell Physiol 305(5):C481-91.

siRNA:

  1. iCell Products: Applying Transfection Technologies to Create Novel Screening Models. Cellular Dynamics Application Note.
  2. Traister A, Li M, et al. (2014) Integrin-linked Kinase Mediates Force Transduction in Cardiomyocytes by Modulating SERCA2a/PLN Function. Nature Comm 5:4533.
  3. Fine M, Lu F, et al. (2013) Human Induced Pluripotent Stem Cell-derived Cardiomyocytes for Studies of Cardiac Ion Transporters. Am J Physiol Cell Physiol 305(5):C481-91.

Reporter Vector Expression:

  1. Robers M and Jarecki B. (2014) Efficiently Build Relevant In Vitro Models Using Human Stem Cell-derived Tissue Cells, High Performance Transfection and Novel Multiplexed Reporter Techniques. Promega/Cellular Dynamics Webinar.

Monitoring Cardiotoxicity

Measurements of cell health are a fundamental component of any disease research and drug development effort.

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Monitoring Cardiotoxicity

Discovery, Toxicity

Measurements of cell health are a fundamental component of any disease research and drug development effort. Cell health endpoints represent various biological processes including cell morphology, viability, cytotoxicity, apoptosis, and mitochondrial integrity. In drug development, researchers interrogate these endpoints as part of discovery screening efforts as well as toxicity studies. CDI’s cardiomyocytes have been utilized to measure various cardiac cell health endpoints using platforms including:

Plate-based Fluorescent and Luminescent Assays:

  1. Robers M and Jarecki B. (2014) Efficiently Build Relevant In Vitro Models Using Human Stem Cell-derived Tissue Cells, High Performance Transfection and Novel Multiplexed Reporter Techniques. Promega/Cellular Dynamics Webinar.
  2. Evans NJ, Kirkland TA, et al. (2012) A Multiplexed, Bioluminescent HDAC Assay for Determining Target-specific, Anti-cancer Potency. Poster Presentation, AACR.
  3. Reynolds JG, Geretti E, et al. (2012) HER2-targeted Liposomal Doxorubicin Displays Enhanced Anti-tumorigenic Effects without Associated Cardiotoxicity. Toxicol Appl Pharmacol 262(1):1-10.

Metabolism Analysis:

  1. Performing Bioenergetic Analysis: X96 Extracellular Flux Analyzer. Cellular Dynamics Application Protocol.
  2. Rana P, Anson BD, et al. (2012) Characterization of Human-induced Pluripotent Stem Cell-derived Cardiomyocytes: Bioenergetics and Utilization in Safety Screening. Toxicol Sci 130(1):117-31.

High Content Analysis:

  1. Sirenko O, Cromwell EF, et al. (2013) Assessment of Beating Parameters in Human Induced Pluripotent Stem Cells Enables Quantitative In Vitro Screening for Cardiotoxicity. Toxicol Appl Pharmacol 273(3):500-07.
  2. Mioulane M, Foldes G, et al. (2012) Development of High Content Imaging Methods for Cell Death Detection in Human Pluripotent Stem Cell-derived Cardiomyocytes. J Cardiovasc Trans Res 5(5):593-604.
  3. Schweikart K, Guo L, et al. (2013) The Effects of Jaspamide on Human Cardiomyocyte Function and Cardiac Ion Channel Activity. Toxicol In Vitro 27(2):745-51.

Impedance Measurement:

  1. Talbert DR, Doherty KR, et al. (2014) A Multi-parameter In Vitro Screen in Human Stem Cell-derived Cardiomyocytes Identifies Ponatinib-Induced Structural and Functional Cardiac Toxicity. Toxicol Sci 143(1):147-55.
  2. Doherty K, Wappel R, et al. (2013) Multi-parameter In Vitro Toxicity Testing of Crizotinib, Sunitinib, Erlotinib, and Nilotinib in Human Cardiomyocytes. Toxicol Appl Pharmacol 272(1):245-55.
  3. Cameron BJ, Gerry AB, et al. (2013) Identification of a Titin-derived HLA-A1-presented Peptide as a Cross-reactive Target for Engineered MAGE A3-directed T Cells. Sci Transl Med 5(197):197ra103.
  4. Cohen JD, Babiarz JE, et al. (2011) Use of Human Stem Cell-derived Cardiomyocytes to Examine Sunitinib Mediated Cardiotoxicity and Electrophysiological Alterations. Toxicol Appl Pharmacol 257(1):74-83.
  5. Schweikart K, Guo L, et al. (2013) The Effects of Jaspamide on Human Cardiomyocyte Function and Cardiac Ion Channel Activity. Toxicol In Vitro 27(2):745-51.

Measuring Cardiomyocyte Electrophysiology

The dysregulation of ion channel function and electrical signaling is a key cause of congenital, environmental, and drug-induced cardiac dysfunction.

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Measuring Cardiomyocyte Electrophysiology

Discovery, Toxicity

The dysregulation of ion channel function and electrical signaling is a key cause of congenital, environmental, and drug-induced cardiac dysfunction. CDI’s cardiomyocytes recapitulate in vivo cardiac function and have demonstrated utility in monitoring electrical activity at molecular, cellular, and organotypic levels using platforms including:

Manual Patch Clamp:

  1. Measuring Cardiac Electrical Activity: Manual Perforated Patch Clamp. Cellular Dynamics Application Protocol.
  2. Gibson JK, Yue Y, et al. (2014) Human Stem Cell-derived Cardiomyocytes Detect Drug-mediated Changes in Action Potentials and Ion Currents. J Pharmacol Toxicol Methods 70(3):255-67.
  3. Jehle J, Ficker E, et al. (2013) Mechanisms of Zolpidem-induced Long QT Ayndrome: Acute Inhibition of Recombinant hERG K+ Channels and Action Potential Prolongation in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells. Br J Pharmacol 168(5):1215-29.
  4. Ivashchenko CY, Pipes GC, et al. (2013) Human-induced Pluripotent Stem Cell-derived Cardiomyocytes Exhibit Temporal Changes in Phenotype. Am J Physiol Heart Circ Physiol 305(6):H913-22.
  5. Wei H, Zhang G, et al. (2012) Hydrogen Sulfide Suppresses Outward Rectifier Potassium Currents in Human Pluripotent Stem Cell-derived Cardiomyocytes. PloS One 7(11):e50641.
  6. Ma J, Guo L, et al. (2011) High Purity Human-induced Pluripotent Stem Cell-derived Cardiomyocytes: Electrophysiological Properties of Action Potentials and Ionic Currents. Am J Physiol Heart Circ Physiol 301(5):H2006-H2017.
  7. Fine M, Lu F, et al. (2013) Human Induced Pluripotent Stem Cell-derived Cardiomyocytes for Studies of Cardiac Ion Transporters. Am J Physiol Cell Physiol 305(5):C481-91.

Automated Patch Clamp:

  1. Ma J, Guo L, et al. (2011) High Purity Human-induced Pluripotent Stem Cell-derived Cardiomyocytes: Electrophysiological Properties of Action Potentials and Ionic Currents. Am J Physiol Heart Circ Physiol 301(5):H2006-H2017.
  2. Cohen JD, Babiarz JE, et al. (2011) Use of Human Stem Cell-derived Cardiomyocytes to Examine Sunitinib Mediated Cardiotoxicity and Electrophysiological Alterations. Toxicol Appl Pharmacol 257(1):74-83.
  3. Schroder R, Christensen MT, et al. (2013) Exploring Stem Cell-derived Cardiomyocytes with Automated Patch Clamp Techniques. Poster Presentation, Sophion User Meeting.

MEA:

  1. Measuring Cardiac Electrical Activity: Field Potential Detection on the Maestro Multielectrode Array. Cellular Dynamics Application Protocol. [iCell Cardiomyocytes]
  2. Measuring Cardiac Electrical Activity: Field Potential Detection on the Maestro Multielectrode Array. Cellular Dynamics Application Protocol. [iCell Cardiomyocytes2]
  3. Harris K, Aylott M, et al. (2013) Comparison of Electrophysiological Data from Human Induced Pluripotent Stem Cell Derived Cardiomyocytes (hiPSC-CMs) to Functional Pre-clinical Safety Assays. Toxicol Sci 134(2):412-26.
  4. Guo L, Coyle L, et al. (2013) Refining the Human iPSC-cardiomyocyte Arrhythmic Risk Assessment Model. Toxicol Sci 136(2):581-94.

Voltage Sensitive Dyes:

  1. Lee P, Kloss M, et al. (2012) Simultaneous Voltage and Calcium Mapping of Genetically Purified Human Induced Pluripotent Stem Cell-derived Cardiac Myocyte Monolayers. Circ Res 110(12):1556-63.
  2. Zamora V, Hortigon‐Vinagre MP, et al. (2014) Rapid Intensity Modulation of a Single Light Source Allows Excitation of Voltage Sensitive Dye and Intermittent Activation of Channel Rhodopsin in hiPSC Derived Cardiomyocytes (hiPSC‐CMs). Poster Presentation, SPS.

 

Measuring Cardiomyocyte Contractility

The modulation of cardiomyocyte contraction (inotropy) is an important phenotypic endpoint for drug discovery, both in the context of intended outcomes and adverse side effects.

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Measuring Cardiomyocyte Contractility

Discovery, Toxicity

The modulation of cardiomyocyte contraction (inotropy) is an important phenotypic endpoint for drug discovery, both in the context of intended outcomes and adverse side effects. CDI’s cardiomyocytes have been used to perform direct measurement of cellular movement or indirect measurement of changes in cell morphology using platforms including:

Detecting Cardiomyocyte Arrhythmia

The development of cardiac arrhythmias as an unintended pharmacological side effect is the most common cause of drug withdrawal and restrictions placed on marketed drugs.

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Detecting Cardiomyocyte Arrhythmia

Discovery, Toxicity

The development of cardiac arrhythmias as an unintended pharmacological side effect is the most common cause of drug withdrawal and restrictions placed on marketed drugs. CDI’s cardiomyocytes have emerged as the most physiologically relevant and predictive human in vitro model system for detecting drug-mediated arrhythmias. Researchers have demonstrated the utility of these cardiomyocytes for this application using platforms including:

  1. Measuring Cardiac Activity: Intracellular Calcium Flux Detection on the FLIPR Tetra System. Cellular Dynamics Application Protocol.
  2. Measuring Cardiac Activity: Impedance Detection with xCELLigence RTCA Cardio System, Cellular Dynamics Application Protocol. [iCell Cardiomyocytes]
  3. Measuring Cardiac Activity: Impedance Detection with xCELLigence RTCA Cardio System, Cellular Dynamics Application Protocol. [iCell Cardiomyocytes2]
  4. Measuring Cardiac Electrical Activity: Field Potential Detection on the Maestro Multielectrode Array. Cellular Dynamics Application Protocol. [iCell Cardiomyocytes)
  5. Measuring Cardiac Electrical Activity: Field Potential Detection on the Maestro Multielectrode Array. Cellular Dynamics Application Protocol. [iCell Cardiomyocytes2]
  6. Measuring Cardiac Electrical Activity: Field Potential Detection with Multielectrode Array. Cellular Dynamics Application Protocol.
  7. Sirenko O, Cromwell EF, et al. (2013) Assessment of Beating Parameters in Human Induced Pluripotent Stem Cells Enables Quantitative In Vitro Screening for Cardiotoxicity. Toxicol Appl Pharmacol 273(3):500-07.
  8. Guo L, Abrams RM, et al. (2011) Estimating the Risk of Drug-induced Proarrhythmia Using Human Induced Pluripotent Stem Cell-derived Cardiomyocytes. Toxicol Sci 123(1):281-289.
  9. Jehle J, Ficker E, et al. (2013) Mechanisms of Zolpidem-induced Long QT Ayndrome: Acute Inhibition of Recombinant hERG K+ Channels and Action Potential Prolongation in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells. Br J Pharmacol 168(5):1215-29.
  10. Cerignoli R, Charlot D, et al. (2012) High Throughput Measurement of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-derived Cardiomyocytes by Kinetic Image Cytometry. J Pharmacol Toxicol Methods 66(3):246-56.
  11. Hayakawa T, Kunihiro T, et al. (2014) Image-based Evaluation of Contraction–Relaxation Kinetics of Human-induced Pluripotent Stem Cell-derived Cardiomyocytes: Correlation and Complementarity with Extracellular Electrophysiology. J Mol Cell Cardiol 77:178-91.
  12. Kattman S and Whittaker R. (2014) Efficient Detection and Prediction of Drug-induced Cardiac Arrhythmias. Cellular Dynamics/Vala Sciences Webinar.

Measuring Intracellular Signaling in Cardiomyocytes

Various intracellular Ca2+ and phosphorylation-mediated signaling pathways play a central role in translating electrical signals at the cell membrane into physical contractile function.

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Measuring Intracellular Signaling in Cardiomyocytes

Discovery, Toxicity

Various intracellular Ca2+ and phosphorylation-mediated signaling pathways play a central role in translating electrical signals at the cell membrane into physical contractile function. These pathways can be measured in CDI’s cardiomyocytes using platforms including:

Modeling Cardiac Hypertrophy

Cardiac hypertrophy can occur in response to various pathological stimuli and is characterized by cellular changes including reactivation of the fetal gene program, increases in cellular volume...

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Modeling Cardiac Hypertrophy

Discovery, Disease Modeling

Cardiac hypertrophy can occur in response to various pathological stimuli and is characterized by cellular changes including reactivation of the fetal gene program, increases in cellular volume, and reorganization of the cytoskeleton. Using CDI’s cardiomyocytes, researchers can induce the hypertrophic condition in vitro using stimuli, such as endothelin-1, and measured by phenotypic endpoints including:

  • BNP gene expression by qRT-PCR
  • BNP protein expression by flow cytometry
  • BNP protein expression by HCA
  • BNP protein secretion by ELISA

Modeling Hypoxia

Myocardial ischemia is a pathological condition characterized by reduced oxygen supply (hypoxia) that can lead to cell death, arrhythmia, organ injury, and death.

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Modeling Hypoxia

Discovery, Disease Modeling

Myocardial ischemia is a pathological condition characterized by reduced oxygen supply (hypoxia) that can lead to cell death, arrhythmia, organ injury, and death. Ironically, returning hypoxic myocardium to normoxic levels exacerbates the pathology (collectively known as myocardial reperfusion injury). CDI’s cardiomyocytes are amenable to hypoxia induction, measurement of hypoxia-induced functional endpoints, and screening for cardioprotective agents.

Modeling Diabetic Cardiomyopathy

Diabetic cardiomyopathy is a complication of type 2 diabetes that results from lifestyle and genetic conditions.

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Modeling Diabetic Cardiomyopathy

Discovery, Disease Modeling

Diabetic cardiomyopathy is a complication of type 2 diabetes that results from lifestyle and genetic conditions. CDI’s cardiomyocytes have been used to develop environmental and patient-specific in vitro models that recapitulate this complex metabolic condition. These models are employed in a phenotypic screening assay resulting in the identification of candidate protective molecules.

Advanced Neural Cell Culture

Advanced cell culture techniques including 3D spheroids, micropatterned co-culture, bioengineered and flow-based systems, and bioprinting offer the potential to better mimic in vivo tissue structure and function.

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Advanced Neural Cell Culture

Discovery, Regenerative Medicine, Toxicity

Advanced cell culture techniques including 3D spheroids, micropatterned co-culture, bioengineered and flow-based systems, and bioprinting offer the potential to better mimic in vivo tissue structure and function. CDI’s neurons are amenable to these culture techniques as pure cell populations or in co-culture with other cell types, such as CDI’s astrocytes.

  1. Carlson C, Wang J, et al. (2014) Characterization of an Isogenic Disease Model of Alzheimer’s Disease from Human iPSC-derived Neurons. Poster Presentation, Society for Neuroscience.
  2. DeLaura S, Fluri DA, et al. (2014) Human Neural Microtissues Derived from Induced Pluripotent Stem Cells for Toxicity Testing. Poster Presentation, Society for Neuroscience.

Genetic Manipulation of Neurons

The ability to interrogate and monitor gene expression is critical to understanding biological pathways that underlie normal and pathogenic cellular function.

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Genetic Manipulation of Neurons

Discovery, Regenerative Medicine, Toxicity

The ability to interrogate and monitor gene expression is critical to understanding biological pathways that underlie normal and pathogenic cellular function. CDI’s neurons and dopaneurons are amenable to various genetic manipulation techniques including:

  • Transfection
  • Transduction
  • siRNA
  • Reporter vector expression

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