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January 2014

Dage JL, Colvin EM, Fouillet A, Langron E, Roell WC, Li J, Mathur SX, Mogg AJ, Schmitt MG, Felder CC, Merchant KM, Isaac J, Broad LM, Sher E, and Ursu D

Pharmacological Characterisation of Ligand- and Voltage-gated Ion Channels Expressed in Human iPSC-derived Forebrain Neurons

Psychopharmacology (Berl) 231(6):1105-24

Publication Date: January 7, 2014

Product Type: iCell GABANeurons

Summary:

Gene expression analysis and functional characterization (using FLIPR) of the ion channels (Ca and Na) and receptors (AMPA, NMDA, and GAB) involved in synaptic physiology were performed on iCell Neurons.

Impact:

This study demonstrated that iCell Neurons show higher correlation with the prefrontal cortex and they exhibit functional ionotropic glutamate receptors (AMPA and NMDA) and GABAA receptors. iCell Neurons are a good cellular model of a forebrain human neuron population that can be used both as a control or host of genetic mutations in genetic neurological disease studies (ASD).

Odawara A, Saitoh Y, Alhebshi AH, Gotoh M, and Suzuki I

Long-term Electrophysiological Activity and Pharmacological Response of a Human Induced Pluripotent Stem Cell-derived Neuron and Astrocyte Co-culture

Biochem Biophys Res Commun 443(4):1176-81

Publication Date: January 7, 2014

Product Type: iCell GABANeurons

Summary:

iCell Neurons were co-cultured with rat primary astrocytes to study the effects of a co-culture environment on the longevity, spontaneous firing activity and drug response on the neurons as measured by MEA.

Impact:

iCell Neurons were maintained in culture with the rat astrocytes for an extend period of time (>120 days) and they were able to maintain long-term spontaneous firing that can be modulated with synapse antagonists drugs and detect synchronicity.

December 2013

Rao C, Prodromakis T, Kolker L, Chaudhry UA, Trantidou T, Sridhar A, Weekes C, Camelliti P, Harding SE, Darzi A, Yacoub MH, Athanasiou T, and Terracciano CM

The Effect of Microgrooved Culture Substrates on Calcium Cycling of Cardiac Myocytes Derived from Human Induced Pluripotent Stem Cells

Biomaterials 34(10):2399-411

Publication Date: December 20, 2013

Product Type: iCell Cardiomyocytes

Summary:

Cellular alignment, sarcomeric organization, and Ca2+ cycling properties were altered when iCell Cardiomyocytes were cultured on a structured substrate.

Impact:

This manuscript is an example of the value in combining advanced cell culture techniques with advanced cellular biology can create a more robust recapitulation of native cellular behavior.

Uesugi M, Ojima A, Taniguchi T, Miyamoto N, and Sawada K

Low-density Plating Is Sufficient to Induce Cardiac Hypertrophy and Electrical Remodeling in Highly Purified iPS Cell-derived Cardiomyocytes

J Pharmacol Toxicol Methods 69(2):177-88

Publication Date: December 1, 2013

Product Type: iCell Cardiomyocytes

Summary:

Cardiac hypertrophy was induced in iCell Cardiomyocytes through low-density plating. The hypertrophic condition resulted in larger cardiomyocytes and altered gene and protein expression profiles.

Impact:

This body of work demonstrates that iCell Cardiomyocytes can be induced to show relevant and appropriate pathological responses and provide utility as an in vitro model for understanding and treating cardiac disease.

November 2013

Sirenko O, Hesley J, Rusyn I, and Cromwell EF

High-content Assays for Hepatotoxicity Using Induced Pluripotent Stem Cell-derived Cells

Assay Drug Dev Technol 12(1):43-54

Publication Date: November 14, 2013

Product Type: iCell Hepatocytes

Summary:

iCell Hepatocytes were employed in the screening of a panel of 208 known hepatotoxic and 30 safe compounds by high content analysis for multiple toxic endpoint readouts.

Impact:

The predictive power of the iCell Hepatocytes in assessing compound hepatotoxicity suggests their utility as in vitro assay models for toxicity screening and understanding potential hepatotoxic effects early in the drug development process.

October 2013

Sirenko O, Cromwell EF, Crittenden C, Wignall JA, Wright FA, and Rusyn I

Assessment of Beating Parameters in Human Induced Pluripotent Stem Cells Enables Quantitative In Vitro Screening for Cardiotoxicity

Toxicol Appl Pharmacol 273(3):500-07

Publication Date: October 1, 2013

Product Type: iCell Cardiomyocytes

Summary:

High-throughput protein-based assays were developed with iCell Cardiomyocytes as a system to induce and ameliorate hypertrophy.

Impact:

This research demonstrates the practicality and utility of utilizing relevant native human biology in disease modeling and high throughput screens for drug discovery.

September 2013

Carlson C, Koonce C, Aoyama N, Einhorn S, Fiene S, Thompson A, Swanson B, Anson B, and Kattman S

Phenotypic Screening with Human iPS Cell-derived Cardiomyocytes: HTS-compatible Assays for Interrogating Cardiac Hypertrophy

J Biomol Screen 18(10):1203-11

Publication Date: September 26, 2013

Product Type: iCell Cardiomyocytes

Summary:

High-throughput protein-based assays were developed with iCell Cardiomyocytes as a system to induce and ameliorate hypertrophy.

Impact:

This research demonstrates the practicality and utility of utilizing relevant native human biology in disease modeling and high-throughput screens for drug discovery.

Guo L, Coyle L, Abrams RM, Kemper R, Chiao ET, and Kolaja KL

Refining the Human iPSC-cardiomyocyte Arrhythmic Risk Assessment Model

Toxicol Sci 136(2):581-94

Publication Date: September 19, 2013

Product Type: iCell Cardiomyocytes

Summary:

iCell Cardiomyocytes were able to predict QT prolongation and arrhythmia with greater accuracy than current in vitro models when challenged with a set of 118 public and proprietary compounds.

Impact:

This study demonstrates that iCell Cardiomyocytes provide improved proarrhythmia predictions on a higher throughput screening platform thus providing value-added data with fewer resources.

August 2013

Cameron BJ, Gerry AB, Dukes J, Harper JV, Kannan V, Bianchi FC, Grand F, Brewer JE, Gupta M, Plesa G, Bossi G, Vuidepot A, Powlesland AS, Legg A, Adams KJ, Bennett AD, Pumphrey NJ, Williams DD, Binder-Scholl G, Kulikovskaya I, Levine BL, Riley JL, Varela-Rohena A, Stadtmauer EA, Rapoport AP, Linette GP, June CH, Hassan NJ, Kalos M, and Jakobsen BK

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

Publication Date: August 7, 2013

Product Type: iCell Cardiomyocytes

Summary:

A T cell-based adoptive immunotherapy was developed and deemed to be free of off-target recognition or safety worries by extensive preclinical investigations. Administration to humans resulted in separate severe cardiotoxicity-related adverse event and fatality. Subsequent investigations showed cross-reactivity with cardiac Titin in a highly species-specific manner that was detectable in iCell Cardiomyocytes but not primary cultures of human cardiac cells maintained under the same conditions.

Impact:

This research demonstrates the need for culture systems that more fully recapitulate the native condition, even for highly specific immune-based drug discovery efforts.

Whitemarsh RC, Tep WH, Bradshaw M, Lin G, Pier CL, Scherf JM, Johnson EA, and Pellett S

Characterization of Botulinum Neurotoxin A Subtypes 1 through 5 by Investigation of Activities in Mice, in Neuronal Cell Cultures, and In Vitro

Infect Immun 81(10):3894-902

Publication Date: August 5, 2013

Product Type: iCell GABANeurons

Summary:

iCell Neurons, along with other commonly used in vitro and in vivo models, were used to characterize the various subtypes of BoNT/A. The results showed distinct in vitro and in vivo toxicological properties between the mouse bioassay (MBA) and in vitro human cell models, thus questioning the predictivity of the MBA.

Impact:

This study supports the need to consider not only the mode of the testing (in vivo versus in vitro) but also the species of the model when designing potency assays for current and future pharmaceutical BoNT preparations. iCell Neurons area relevant human model to detect BoNT.

July 2013

Ivashchenko CY, Pipes GC, Lozinskaya IM, Lin Z, Xiaoping X, Needle S, Grygielko ET, Hu E, Toomey JR, Lepore JJ, and Willette RN

Human-induced Pluriopotent Stem Cell-derived Cardiomyocytes Exhibit Temporal Changes in Phenotype

Am J Physiol Heart Circ Physiol 305(6):H913-22

Publication Date: July 5, 2013

Product Type: iCell Cardiomyocytes

Summary:

In culture, iCell Cardiomyocytes progressively develop a more mature phenotype without signs of dedifferentiation. This phenotype is characterized by adult-like gene expression patterns, action potentials exhibiting ventricular atrial and nodal properties, coordinated calcium cycling and mechanical activity with pharmacological responses to pathologic (ET-1), physiologic (IGF-1) and autonomic (isoproterenol) stimuli similar to those characteristic of isolated adult cardiac myocytes.

Impact:

This study demonstrates that iCell Cardiomyocytes recapitulate native tissue characteristics.

June 2013

Fine M, Lu FM, Lin MJ, Moe O, Wang HR, and Hilgemann DW

Human Induced Pluripotent Stem Cell-derived Cardiomyocytes for Studies of Cardiac Ion Transporters

Am J Physiol Cell Physiol 305(5):C481-91

Publication Date: June 26, 2013

Product Type: iCell Cardiomyocytes

Summary:

iCell Cardiomyocytes were analyzed for cardiac ion transporter function. Data demonstrate that iCell Cardiomyocytes exhibit human adult-like expression of major cardiac ion transporters, are amenable to long-term molecular manipulation of individual transporter and regulatory proteins, and can be used for analysis of transporter and regulatory protein turnover.

Impact:

Data support the use of iCell Cardiomyocytes for a wide range of new cellular and molecular experimentation that was previously not possible to elucidate the molecular function and regulation of ion transporters.

Grose C, Yu X, Cohrs RJ, Carpenter JE, Bowlin JL, and Gilden D

Aberrant Virion Assembly and Limited Glycoprotein C Production in Varicella-Zoster Virus-infected Neurons

J Virol 87(17):9643-8

Publication Date: June 26, 2013

Product Type: iCell GABANeurons

Summary:

An iCell Neurons in vitro model of varicella zoster virus (VZV) infection developed by Yu, et al. (2013) was used in a subsequent study to determine whether diminished production of virion components and/or final assembly of complete virions play a role in limiting productive virus infection.

Impact:

Primary VZV infection typically produces varicella (chickenpox), after which the virus becomes latent. Reactivation of the virus produces zoster (shingles), which is a more serious disease characterized by chronic pain and other neurological problems. iCell Neurons are used to model VZV infection and better define the molecular underpinnings of the virus-host relationship.

May 2013

Doherty KR, Wappel RL, Talbert DR, Trusk PB, Moran DM, Kramer JW, Brown AM, Shell SA, and Bacus S

Multiparameter In Vitro Toxicity Testing of Crizotinib, Sunitinib, Erlotinib, and Nilotinib in Human Cardiomyocytes

Toxicol Appl Pharmacol 272(1):245-55

Publication Date: May 21, 2013

Product Type: iCell Cardiomyocytes

Summary:

Tyrosine kinase inhibitors (TKi) have an established therapeutic value but also have associated cardiotoxicity that is not detected by standard pre-clinical models. iCell Cardiomyocytes and multiparametric analysis correctly predicted the cardiotoxic profile of four FDA-approved TKi molecules that showed unexpected toxicity in humans.

Impact:

The data here demonstrate the value of utilizing functional human cardiac biology in pre-clinical testing to alleviate and avoid costly adverse events in clinical trials and the general population.

Harris K, Aylott M, Cui Y, Louttit JB, McMahon NC, and Sridhar A

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

Publication Date: May 20, 2013

Product Type: iCell Cardiomyocytes

Summary:

Analysis of the cardiotoxic responses to known ion channel blockers and proprietary GSK compounds using iCell Cardiomyocytes and a multielectrode array (MEA) platform. iCell Cardiomyocytes demonstrate relevant pharmacology that correlates with existing pre-clinical assays.

Impact:

This is the first study to demonstrate that in addition to showing relevant human physiology and pharmacology, iCell Cardiomyocytes’ responses to known cardiotoxic agents correlate to existing pre-clinical assays. Translation between novel iCell Cardiomyocytes assays and other pre-clinical assays is critical for drug discovery and safety studies to be considered in the regulatory environment.

April 2013

Khan JM, Lyon AR, and Harding SE

The Case for Induced Pluripotent Stem Cell-derived Cardiomyocytes in Pharmacological Screening

Br J Pharmacol 169(2):304-17

Publication Date: April 26, 2013

Product Type: iCell Cardiomyocytes

Summary:

This review assesses state-of-the art technology as of 2013, noting the advantages, potentials, and limitations of stem cell-derived cardiomyocytes in pharmacological screening.

Impact:

The data and references within this review provide readers with peer-reviewed demonstrations of stem cell-derived cardiomyocyte utility. Many of the shortcomings and/or gaps in the technology are being (or have been) addressed by CDI.

February 2013

Jehle J, Ficker E, Wan X, Deschenes I, Kisselbach J, Wiedmann F, Staudacher I, Schmidt C, Schweizer PA, Becker R, Katus HA, and Thomas D

Mechanisms of Zolpidem-induced Long QT Syndrome: 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

Publication Date: February 21, 2013

Product Type: iCell Cardiomyocytes

Summary:

iCell Cardiomyocytes exhibited prolongation of cardiac action potential duration in response to zolpidem, a short-acting hypnotic drug prescribed to treat insomnia that has been clinically associated with acquired long QT syndrome (LQTS) and torsade de pointes (TdP).

Impact:

iCell Cardiomyocytes treated with a known toxic drug compound showed biochemical responses that mimic toxic responses observed in the clinic, demonstrating that iCell Cardiomyocytes are a relevant in vitro model to predict human cardiotoxicity.

January 2013

Gill JK, Chatzidaki A, Ursu D, Sher E, and Millar NS

Contrasting Properties of α7-Selective Orthosteric and Allosteric Agonists Examined on Native Nicotinic Acetylcholine Receptors

PLoS One 8(1):e55047

Publication Date: January 29, 2013

Product Type: iCell GABANeurons

Summary:

iCell Neurons were used to evaluate the potential use of three pharmacologically distinct α7-selective nicotinic ligands (an orthosteric agonist, a positive allosteric modulator, and a nondesensitizing allosteric agonist) for the characterization of native nAChRs.

Impact:

iCell Neurons were shown to be a relevant human model to identify and characterize ligands that are specific for particular receptor subtypes implicated in neurological and psychiatric disorders. The identification of such reagents will accelerate academic research and pharmaceutical drug discovery.

December 2012

Schweikart K, Guo L, Shuler Z, Abrams R, Chiao ET, Kolaja KL, and Davis M

The Effects of Jaspamide on Human Cardiomyocyte Function and Cardiac Ion Channel Activity

Toxicol In Vitro 27(20:745-51

Publication Date: December 20, 2012

Product Type: iCell Cardiomyocytes

Summary:

iCell Cardiomyocytes were used to demonstrate that the acute clinical toxicity of jaspamide, an anti-neoplastic agent, is due to drug-induced cardiotoxicity.

Impact:

iCell Cardiomyocytes were used to elucidate mechanisms of action of an anti-cancer drug associated with clinical toxicity.

Yu X , Seitz S, Pointon T, Bowlin JL, Cohrs RJ, Jonjić S, Haas J, Wellish M, and Gilden D

Varicella Zoster Virus Infection of Highly Pure Terminally Differentiated Human Neurons

J Neurovirol 19(1):75-81

Publication Date: December 12, 2012

Product Type: iCell GABANeurons

Summary:

iCell Neurons were used to develop a novel in vitro model of varicella zoster virus (VZV) infection. Infection of iCell Neurons with VZV yields a non-productive infection with detectable expression of immediate-early, early, and late viral genes, but no evidence of apoptosis, which together will enable molecular analysis of VZV-neuron interactions and mechanisms of VZV reactivation.

Impact:

iCell Neurons provided 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.