Applications

Toxicity

Increased Predictivity in Toxicity Testing

The assessment of new pharmaceuticals and chemicals is a complex process that incorporates information from in silico analyses, in vitro studies, and animal testing. Several recent events have led to an increased need for validated, physiologically relevant, and predictive human in vitro models:

  • High attrition rate of new drugs in development
  • Withdrawal of marketed drugs due to toxicity
  • Increased focus on animal welfare issues due to legislative changes

iCell® and MyCell® Products offer a novel approach to in vitro safety testing that overcomes many limitations of existing models. Benefits include:

  • Biologically relevant human cell models
  • Highly reproducible to ensure confidence in results
  • Consistent availability to eliminate the need for repeat sourcing and validation

The importance of iCell and MyCell products to the future of safety assessment is best evidenced by a proposed new regulatory paradigm to validate and standardize the use of stem cell-derived cardiomyocytes in in vitro assays for predicting cardiac arrhythmia.

Browse the growing list of publications that demonstrate the use of iCell products for interrogating mechanisms of toxicity and improving predictivity.

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 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.

Genetic Manipulation of Endothelial Cells

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 Endothelial Cells

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 worked to evaluate a wide range of genetic manipulation tools to enable the development of assays using its endothelial cells.