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October 2014

Drawnel FM, Boccardo S, Prummer M, Delobel F, Graff A, Weber M, Gérard R, Badi L, Kam-Thong T, Bu L, Jiang X, Hoflack JC, Kiialainen A, Jeworutzki E, Aoyama N, Carlson C, Burcin M, Gromo G, Boehringer M, Stahlberg H, Hall BJ, Magnone MC, Kolaja K, Chien KR, Bailly J, and Iacone R

Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy Using Human Induced Pluripotent Stem Cells

Cell Rep 9(3):810-820

Publication Date: October 30, 2014

Product Type: iCell Cardiomyocytes,

Summary:

Researchers created in vitro models for environmental and genetically-driven diabetic cardiomyopathy. iCell Cardiomyocytes were induced to the cardiomyopathic state through incubation with a diabetic medium while diabetic donor-specific, iPSC-derived MyCell Cardiomyocytes showed the cardiomyopathy phenotype under baseline conditions. A small molecule screen identified molecules that reverted the cardiomyopathy in accordance with the clinical progression of the disease.

Impact:

This research validates using human iPSC-derived technology in phenotypic drug discovery. It demonstrates the recapitulation of cardiomyopathy through environmental and genetic mechanisms and establishes the utility of phenotypic screens to find molecules and pathways that may provide a therapeutic option.

September 2014

Aggarwal P, Turner A, Matter A, Kattman SJ, Stoddard A, Lorier R, Swanson BJ, Arnett DK, and Broeckel U

RNA Expression Profiling of Human iPSC-derived Cardiomyocytes in a Cardiac Hypertrophy Model

PLoS One 9(9):e108051

Publication Date: September 25, 2014

Product Type: iCell Cardiomyocytes

Summary:

Cardiac hypertrophy is characterized by phenotypic, molecular, and genomic changes. This work induced hypertrophy in iCell Cardiomyocytes, demonstrated overlap in transcriptional changes between induced iCell Cardiomyocytes and biopsied cardiac tissue from donor’s with left ventricular hypertrophy, and isolated a unique micro-RNA / mRNA pairing that provided further insight to a complex disease etiology.

Impact:

Most diseases have complex origins and presentations. This work exemplifies the power of iPSC-derived models to recapitulate disease states, elucidate novel molecular entities associated with disease states, and provide insight as to causes and potential therapeutic avenues.

Hayakawa T, Kunihiro T, Ando T, Kobayashi S, Matsui E, Yada H, Kanda Y, Kurokawa J, and Furukawa T

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

Publication Date: September 23, 2014

Product Type: iCell Cardiomyocytes

Summary:

Researchers used label-free imaging for examining contractility. Cross-platform comparison with electrophysiology, intracellular Ca2+, and traction-force microscopy demonstrated appropriate readout. Functional validation with Na+ channel block, hERG channel block, and beta adrenergic stimulation showed utility for examining cardiomyocyte contraction rate, force, and relaxation.

Impact:

Label-free imaging enables investigators to apply quantitative metrics to iCell Cardiomyocytes’ contractility endpoints in a higher throughput fashion.

Scott CW, Zhang X, Abi-Gerges N, Lamore SD, Abassi YA, and Peters MF

An Impedance-based Cellular Assay Using Human iPSC-derived Cardiomyocytes to Quantify Modulators of Cardiac Contractility

Toxicol Sci 142(2):331-8

Publication Date: September 18, 2014

Product Type: iCell Cardiomyocytes

Summary:

iCell Cardiomyocytes and impedance measurements were shown to be a suitable system for assessing drug-induced effects on contractility. This system was more predictive than rat cardiomyocytes, had assay parameters similar to the gold standard system, and provided higher throughput.

Impact:

This research demonstrates the utility of iCell Cardiomyocytes as a screening model for assessing contractility changes.

Gibson JK, Yue Y, Bronson J, Palmer C, and Numann R

Human Stem Cell-derived Cardiomyocytes Detect Drug-mediated Changes in Action Potentials and Ion Currents

J Pharmacol Toxicol Methods 70(3):255-67

Publication Date: September 16, 2014

Product Type: iCell Cardiomyocytes

Summary:

Researchers recorded action potentials from isolated iCell Cardiomyocytes before and after drug exposure. The recorded responses were stable, sensitive, and robust, demonstrating the appropriate human cardiac electrophysiology and pharmacology.

Impact:

Proarrhythmia prediction can be done at the phenotypic and mechanistic level. This paper complements the growing literature on phenotypic prediction with iCell Cardiomyocytes by demonstrating valid underlying mechanistic processes and pharmacology.

Traister A, Li M, Aafaqi S, Lu M, Arab S, Radisic M, Gross G, Guido F, Sherret J, Verma S, Slorach C, Mertens L, Hui W, Roy A, Delgado-Olguín P, Hannigan G, Maynes JT, and Coles JG

Integrin-linked Kinase Mediates Force Transduction in Cardiomyocytes by Modulating SERCA2a/PLN Function

Nat Commun 5:4533

Publication Date: September 11, 2014

Product Type: iCell Cardiomyocytes

Summary:

Integrin-linked kinase (ILK) associates with protein scaffolding involved in mechanotransduction and contractility. iCell Cardiomyocytes were used to verify ILK as a potential therapeutic target; its modulation altered expression levels and function of other proteins in the scaffold, intracellular Ca2+ signaling, and contractility.

Impact:

This research demonstrates the utility of iCell Cardiomyocytes as a model system for target identification, verification, and screening. A target was identified, its value as a therapeutic target confirmed through over-expression and knockdown, and the functional impact assessed through phenotypic assays.

April 2014

Nakamura Y, Matsuo J, Miyamoto N, Ojima A, Ando K, Kanda Y, Sawada K, Sugiyama A, and Sekino Y

Assessment of Testing Methods for Drug-induced Repolarization Delay and Arrhythmias in an iPS Cell–derived Cardiomyocyte Sheet: Multi-site Validation Study

J Pharmacol Sci 124(4):494-501

Publication Date: April 2, 2014

Product Type: iCell Cardiomyocytes

Summary:

The experimental robustness of iCell Cardiomyocytes was tested across three independent laboratories. hERG channel (IKr) block was assessed via MEA-measured field potential duration prolongation in each laboratory and found to be equivalent.

Impact:

These data demonstrate that iCell Cardiomyocytes utilized in standardized protocols provide inter-facility robustness and repeatability.

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.

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.

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.

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.

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.

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