Applications

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High-throughput Screening

Drug failure in the clinic is most often attributed to either unforeseen toxicity or a lack of demonstrated efficacy.

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High-throughput Screening

Discovery

Drug failure in the clinic is most often attributed to either unforeseen toxicity or a lack of demonstrated efficacy. Thus, predictive in vitro models that more accurately reflect in vivo disease states can inform the preclinical processes of drug discovery and development ensuring higher success rate in the eventual clinical setting. CDI’s iCell and MyCell products offer a wide range of innate, engineered, and induced disease models for screening, hit-to-lead, and lead optimization efforts. The cells are amenable to gene modulation and culture in high-density multiwell plates. iCell and MyCell products have been used in high-throughput screens across various disease areas including infectious disease, neurological disorders, diabetes, and cardiomyopathies.

Modeling Hepatitis Infection

Hepatitis infection mediated by HCV and HBV is a common cause of liver disease and failure.

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Modeling Hepatitis Infection

Discovery, Disease Modeling

Hepatitis infection mediated by HCV and HBV is a common cause of liver disease and failure. Developing effective therapies for hepatitis has been limited due to the lack of physiologically relevant human disease models. CDI’s hepatocytes express hepatitis receptors (SR-B1, CD91, occludin, claudin-1), which support uptake and replication of clinically relevant hepatitis virus genotypes. These hepatocytes are being used in large-scale screens for novel therapeutic candidates. CDI offers hepatocytes from multiple donors including one with an IFNL4 function that does not readily clear HCV infection.

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.

Genetic Manipulation of Hepatocytes

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 Hepatocytes

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 has evaluated various genetic manipulation tools to enable the development of assays using its hepatocytes.

Advanced Hepatocyte 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 Hepatocyte 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 hepatocytes are amenable to these culture techniques as pure cell populations or in co-culture with other CDI cell types.

Vascular Tissue Bioengineering

Vascular networks supply organs with oxygen and nutrients, remove waste, and serve generally as the delivery network within the body.

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Vascular Tissue Bioengineering

Discovery, Regenerative Medicine, Toxicity

Vascular networks supply organs with oxygen and nutrients, remove waste, and serve generally as the delivery network within the body. Thus, any bio- or tissue engineering effort should include a vascular framework to support organ function. CDI’s endothelial cells have demonstrated functionality to reform vascular networks in decellularized organs to support de novo organ synthesis as a transplantable tissue for regenerative medicine approaches. In addition, CDI’s endothelial cells have formed complex vascular networks in static- and flow-based bioengineered vascular platforms.

Measuring Vasculogenesis

The ability to modulate vasculogenesis has utility in tissue engineering and repair as well as in oncology therapeutics development aimed at targeting angiogenesis.

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Measuring Vasculogenesis

Discovery, Regenerative Medicine

The ability to modulate vasculogenesis has utility in tissue engineering and repair as well as in oncology therapeutics development aimed at targeting angiogenesis. The processes of endothelial cell migration and invasion and vascular sprouting behavior can be measured using CDI’s endothelial cells using platforms including:

  1. Belair DG, Whisler JA, et al. (2014) Human Vascular Tissue Models Formed from Human Induced Pluripotent Stem Cell Derived Endothelial Cells. Stem Cell Rev. [Epub ahead of print]
  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.

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 Varicella Zoster Virus Infection

CDI's neurons provide a biologically relevant human cell model to study mechanisms of VZV infection, which was previously not possible using primary neuronal cells due to limitations in cell functionality and purity.

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Modeling Varicella Zoster Virus Infection

Discovery, Disease Modeling

CDI’s neurons provide a biologically relevant human cell model to study mechanisms of VZV infection, which was previously not possible using primary neuronal cells due to limitations in cell functionality and purity. Specifically, VZV infection results in a non-productive infection characterized by viral gene expression in the absence of apoptosis. This disease phenotype enables molecular analysis of VZV-neuron interactions and mechanisms of VZV reactivation.

  1. Baird NL, Bowlin JL, et al. (2014) Varicella Zoster Virus DNA Does Not Accumulate in Infected Human Neurons. Virology 458-459:1-3.
  2. Baird NL, Bowlin JL, et al. (2014) Comparison of Varicella-Zoster Virus RNA Sequences in Human Neurons and Fibroblasts. J Virol 88(10):5877-80.
  3. Yu X, Sietz S, et al. (2013) Varicella Zoster Virus Infection of Highly Pure Terminally Differentiated Human Neurons. J Neurovirol 19:75-81.
  4. Grose C, Xiaoli Y, et al. (2013) Aberrant Virion Assembly and Limited Glycoprotein C Production in Varicella-Zoster Virus-Infected Neurons. J Virol 87(17):9643-8.