Applications

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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:

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:

Measuring Hematopoietic Cell Proliferation (CFU/CFC Assays)

The ability to model human hematopoietic cell differentiation is critical for many areas of biomedical research including drug-induced hematopoietic cell toxicity, bone marrow transplant tolerance, cancer immunother

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Measuring Hematopoietic Cell Proliferation (CFU/CFC Assays)

Discovery, Toxicity

The ability to model human hematopoietic cell differentiation is critical for many areas of biomedical research including drug-induced hematopoietic cell toxicity, bone marrow transplant tolerance, cancer immunotherapy, and autoimmune disorders. CDI’s hematopoietic progenitor cells offer access to commercial quantities of highly pure hematopoietic cells, providing reproducible results for these and other research and therapeutic applications.

Measuring Cardiac Progenitor Cell Proliferation and Differentiation

The ability to model human cell and organ developmental pathways is critical to understanding developmental toxicities and disease pathways, and to develop therapeutic strategies for tissue regeneration.

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Measuring Cardiac Progenitor Cell Proliferation and Differentiation

Discovery, Regenerative Medicine, Toxicity

The ability to model human cell and organ developmental pathways is critical to understanding developmental toxicities and disease pathways and to developing therapeutic strategies for tissue regeneration. CDI’s cardiac progenitor cells are multipotent cardiomyocyte precursor cells that exhibit robust and measurable proliferation and differentiation. Assays with these cells are being used in targeted and phenotypic screens to identify therapeutic candidates for cardiac regeneration.

Measuring Drug Metabolism

Drug metabolism is a key function of the human liver and is largely accomplished via the activity of P450 cytochromes and other enzymes within hepatocytes.

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Measuring Drug Metabolism

Toxicity

Drug metabolism is a key function of the human liver and is largely accomplished via the activity of P450 cytochromes and other enzymes within hepatocytes. Understanding drug metabolism pathways is critical to defining the availability of therapeutic agents and identifying toxic metabolites. CDI’s hepatocytes exhibit P450 activity that is sustained for over 7 days in culture. In addition, functional P450 induction in response to known inducers has been demonstrated.

  1. P450-Glo Assays. Promega Technical Bulletin.

Monitoring Neurotoxicity

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

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Monitoring Neurotoxicity

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 and toxicity studies. CDI’s neurons, dopaneurons, and astrocytes have been utilized to measure various neural cell health endpoints using platforms including:

Monitoring Hepatotoxicity

Unforeseen liver toxicity is a primary mode of clinical failure for drugs in development.

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Monitoring Hepatotoxicity

Toxicity

Unforeseen liver toxicity is a primary mode of clinical failure for drugs in development. The long-term stability of CDI’s hepatocytes in culture affords the opportunity to perform repeat dosing at physiologically relevant concentrations to aid in the identification of drug toxicity. Specific mechanisms of hepatotoxicity, such as cell viability, mitochondrial toxicity, and phospholipidosis, can be measured using platforms including:

  1. Sirenko O, Hesley J, et al. (2014) High-content Assays for Hepatotoxicity Using Induced Pluripotent Stem Cell-derived Cells. Assay Drug Dev Technol 12(1):43-54.
  2. Berger DR, Ware BR, et al. (2014) Enhancing the Functional Maturity of iPSC-derived Human Hepatocytes via Controlled Presentation of Cell-Cell Interactions In Vitro. Hepatology 61(4):1370-81.
  3. Einhorn S, Lu J, et al. (2013) Detection of Xenobiotic-induced Hepatotoxicity in Human iPSC-derived Hepatocytes. Poster Presentation, ISSX.
  4. Lu J, Metushi I, et al. (2013) Investigation of Isoniazid DILI Mechanisms in Human Induced Pluripotent Stem Cell Derived Hepatocytes. Poster Presentation, ISSX.
  5. Einhorn S, Salvagiotto G, et al. (2013) Characterization and Function of iPSC derived Hepatocytes for Use in Toxicity. Poster Presentation, SOT.
  6. Mann DA. (2014) Human Induced Pluripotent Stem Cell-derived Hepatocytes for Toxicology Testing. Exp Opin Drug Metab & Toxicol 11(1):1-5.

Measuring Neurite Outgrowth

During development, neurons become assembled into functional networks by growing axons and dendrites that connect synaptically to other neurons.

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Measuring Neurite Outgrowth

Discovery, Toxicity

During development, neurons become assembled into functional networks by growing axons and dendrites that connect synaptically to other neurons. Understanding this process of neurite outgrowth is a major focus of neuroscience research and central to drug discovery efforts in neurodegenerative disease and neurotoxicity studies. CDI’s neurons rapidly form complex cell networks and are an ideal model for assessing neurite outgrowth enhancement, inhibition, and protection with target compounds. These changes can be measured using platforms including:

High Content Analysis:

  1. Assessing Neurite Outgrowth: Quantification with High Content Screening. Cellular Dynamics Application Protocol.
  2. Sherman SP and Bang AG. (2014) High Content Screen for Compounds That Modulate Neurite Outgrowth and Retraction Using Human Induced Pluripotent Stem Cell-derived Neurons. Poster Presentation, ISSCR.
  3. High-content Screening of Neuronal Toxicity Using iPSC-derived Human Neurons. Molecular Devices Application Note.

Plate-based Fluorescence & Luminescence Assays:

  1. Immunofluorescent Labeling. Cellular Dynamics Application Protocol.

Label-free Analysis:

  1. Alcantara S, Garay P, et al. (2014) Development of 96/384-well Kinetic Neurite Outgrowth/Stabilisation Assays in Human iPSC-derived Neurons Using Long Term Live Cell Imaging. Poster Presentation, FENS.

Measuring Vascular Endothelial Cell Barrier Function

The endothelial cell barrier regulates the passage of materials and transit of blood cells into and out of the bloodstream.

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Measuring Vascular Endothelial Cell Barrier Function

Discovery, Toxicity

The endothelial cell barrier regulates the passage of materials and transit of blood cells into and out of the bloodstream. Thus, models of barrier function are relevant for the study of xenobiotic permeability, metastasis, inflammation, and wound healing. Endothelial cells’ barrier function and modulation by agents, such as thrombin, can be measured using impedance platforms (ACEA xCELLigence, Applied BioPhysics ECIS).

  1. Assaying Barrier Function. Cellular Dynamics Application Note.
  2. Assaying Barrier Function: xCELLigence RTCA Cardio System. Cellular Dynamics Application Protocol.

Measuring Neuronal Synaptic Activity

The measurement of neuronal synaptic activity can be accomplished through various signaling pathways.

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Measuring Neuronal Synaptic Activity

Discovery, Toxicity

The measurement of neuronal synaptic activity can be accomplished through various signaling pathways. These pathways can be measured in CDI’s neurons and dopaneurons using platforms including:

Measuring Neuronal Electrophysiology

The communication between neurons and between neurons and other cell types is accomplished through electrical signals.

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Measuring Neuronal Electrophysiology

Discovery, Regenerative Medicine, Toxicity

The communication between neurons and between neurons and other cell types is accomplished through electrical signals. CDI’s neurons exhibit biologically relevant electrical functions typical of primary human cortical neurons including evoked and spontaneous action potentials, inhibitory and excitatory post-synaptic currents, and ion channel pharmacology. These responses can be measured using platforms including:

Measuring Vascular Endothelial Cell Proliferation

The regulation of endothelial cell proliferation plays a fundamental role in vascular remodeling and angiogenesis in normal and pathological conditions.

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Measuring Vascular Endothelial Cell Proliferation

Discovery, Regenerative Medicine, Toxicity

The regulation of endothelial cell proliferation plays a fundamental role in vascular remodeling and angiogenesis in normal and pathological conditions. CDI’s endothelial cells exhibit a dose-dependent proliferation response to VEGF that is sensitive to inhibition by tyrphostin, a selective VEGF receptor inhibitor, as measured using the CellTiter-Glo Assay (Promega).

  1. Assaying Cell Proliferation. Cellular Dynamics Application Note.
  2. Belair D, Carlson C, et al. (2014) Label-free, Real-time Analysis of Endothelial Cell Morphogenesis Using iPSC-derived Endothelial Cells. Poster Presentation, AACR.

Modeling Botulinum Neurotoxin Infection

CDI's neurons provide a functionally relevant human model to measure Clostridium botulinum neurotoxin (BoNT) activity.

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Modeling Botulinum Neurotoxin Infection

Discovery, Disease Modeling, Toxicity

CDI’s neurons provide a functionally relevant human model to measure Clostridium botulinum neurotoxin (BoNT) activity. Compared with primary rat spinal cord cells, CDI’s neurons showed equal or increased sensitivity, improved dose-response, and more complete SNARE protein cleavage in response to BoNT treatment. CDI’s neurons are rapidly being adopted by researchers to study mechanisms of BoNT toxicity and by BoNT manufacturers to replace an expensive and labor-intensive mouse bioassay for potency testing.