Schweikart K, Guo L, et al.
(2012 Dec 20)

Toxicol In Vitro.
In press.

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

Jehle J, Ficker E, et al.
(2012 Oct 12)

British J Pharm
[Epub ahead of print]

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.

Demonstration of cardiac action potential duration prolongation in iCell Cardiomyocytes by 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).

Puppala D, Collis LP, et al.
(2012 Sep 14)

Toxicol Sci
131(1):292-301.

Comparative Gene Expression Profiling in Human Induced Pluripotent Stem Cell Derived Cardiocytes and Human and Cynomolgus Heart Tissue.

Comparison of the gene expression profile of iCell Cardiomyocytes post-thaw over a period of 42 days in culture to human fetal and adult profiles as well as adult cynomolgus nonhuman primate. Evaluation of iCell Cardiomyocytes contractility demonstrated functional and pharmacological correlations with myocytes isolated from adult NHP hearts.

Sirenko O, Crittenden C, et al.
(2012 Sep 12)

J Biomol Screen.
18(1): 39-53.

Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using iPSC Cells.

Assessment of cellular physiology and small molecule effects using iCell Cardiomyocytes in conjunction with the FLIPR platform as a high throughput methodology.

Cerignoli R, Charlot D, et al.
(2012 Aug 25)

J Pharmacol Toxicol Methods
66(3):246-56.

High Throughput Measurement of Ca2+ Dynamics for Drug Risk Assessment in Human Stem Cell-derived Cardiomyocytes by Kinetic Image Cytometry.

Use of a novel kinetic imaging cytometry (KIC) for automated cell-by-cell analyses of iCell Cardiomyocytes via intracellular fluorescence Ca2+ indicators. Intracellular calcium concentration ([Ca2+]i) was measured at 30 ms resolution from hundreds of individual cells/well of 96-well plates in seconds to provide kinetic details on the effects of known cardiotoxic and arrhythmogenic drugs.

Mioulane M, Foldes G, et al.
(2012 Aug 16)

J of Cardiovasc Trans Res
5:593-604.

Development of High Content Imaging Methods for Cell Death Detection in Human Pluripotent Stem Cell-derived Cardiomyocytes.

Use of iCell Cardiomyocytes and other cardiac tissue cells to develop a novel simple and scalable humanized fluorescent assay system to detect nuclear remodeling, mitochondrial status, apoptosis, and necrosis on an automated microscopy platform.

Rana P, Anson BD, et al.
(2012 Jul 27)

Toxicol Sci
130:117-31.

Characterization of Human-induced Pluripotent Stem Cell-derived Cardiomyocytes: Bioenergetics and Utilization in Safety Screening.

Investigation of the bioenergetics of iCell Cardiomyocytes using a variety of energy substrates. When fatty acids are available, iCell Cardiomyocytes utilize fatty acid oxidation to generate ATP. iCell Cardiomyocytes also showed expected responses to mitochondrial toxicants.

Reynolds JG, Geretti E, et al.
(2012 Jul 1)

Toxicol Appl Pharmacol
262:1-10.

HER2-targeted Liposomal Doxorubicin Displays Enhanced Anti-tumorigenic Effects without Associated Cardiotoxicity.

Use of iCell Cardiomyocytes and native cardiomyocytes demonstrate the lack of cardiotoxicity associated with HER-2 targeted liposomal doxorubicin. Data were used in submission of an Investigational New Drug (IND) application.

Zhi D, Irvin MR, et al.
(2012 May 28)

Front Genet
3:92.

Whole-exome Sequencing and an iPSC-derived Cardiomyocyte Model Provides a Powerful Platform for Gene Discovery in Left Ventricular Hypertrophy.

Identification of novel polymorphisms associated with LVH from clinical populations and generation of a novel cellular model of LVH using iCell Cardiomyocytes.

Lee P, Kloss M, et al.
(2012 May 8)

Circ Res
110(12):1556-63.

Simultaneous Voltage and Calcium Mapping of Genetically Purified Human Induced Pluripotent Stem Cell-derived Cardiac Myocyte Monolayers. Circ Res. Published online ahead of print.

Development of a multiparametric imaging system using iCell Cardiomyocytes to simultaneously measure action potential and intracellular calcium wave propagation. The described system can be utilized for the study of arrhythmia mechanisms and offers advantages over commonly used rodent models.

Babiarz JE, Ravon M, et al.
(2012 Jan 4)

Stem Cells
21(11):1956-65.

Determination of the Human Cardiomyocyte mRNA and miRNA Differentiation Network by Fine-scale Profiling.

Detailed comparison of the mRNA and miRNA transcriptomes across differentiating iCell Cardiomyocytes and biopsies from fetal, adult, and hypertensive human hearts.

Jonsson MKB, Wang QD, et al.
(2011 Nov 15)

Assay and Drug Dev Tech
9 (6):1-11.

Impedance-Based Detection of Beating Rhythm and Proarrhythmic Effects of Compounds on Stem Cell-derived Cardiomyocytes.

Demonstration of the utility of impedance-based measurements to detect compound effects on beating frequency and arrhythmias using iCell Cardiomyocytes with the xCELLigence RTCA Cardio System (Roche Applied Science). Using this system, the beating frequency of iCell Cardiomyocyte monolayers was stably recorded over several days, and the system detected changes in beating frequency and amplitude in response to reference compounds.

Ma J, Guo L, et al.
(2011 Sep 2)

Am J Physiol Heart Circ Physiol
301:H2006-H2017.

High Purity Human-induced Pluripotent Stem Cell-derived Cardiomyocytes: Electrophysiological Properties of Action Potentials and Ionic Currents.

Characterization study demonstrating that iCell Cardiomyocytes display cellular electrophysiological properties similar to human cardiomyocytes.

Cohen JD, Babiarz JE, et al.
(2011 Aug 27)

Toxicol Appl Pharmacol
257:74-83.

Use of Human Stem Cell Derived Cardiomyocytes to Examine Sunitinib Mediated Cardiotoxicity and Electrophysiological Alterations.

Elucidation of the molecular mechanisms of sunitinub-induced cardiotoxicity. A role for AMP-activated protein kinase (AMPK) and ribosomal 6 kinase (RSK) was hypothesized based on rodent models. However, data generated using human iCell Cardiomyocytes indicate that AMPK and RSK are not major components of sunitinib-induced cardiotoxicity, which is likely due to the simultaneous inhibition of multiple kinases.

Estimating the Risk of Drug-Induced Proarrhythmia Using Human Induced Pluripotent Stem Cell-derived Cardiomyocytes.

Analysis of 28 compounds with known cardiac effects was performed using iCell Cardiomyocytes and the xCELLigence RTCA Cardio System (Roche Applied Science). Compound-specific changes in beat rate and/or the amplitude of the impedance measurement were detected in concordance with clinical findings. These results were confirmed using iCell Cardiomyocytes and the multielectrode array (MEA) platform.

Guo L, Qian JY, et al.
(2011 Jun 15)

Cell Physiol Biochem
27 (5):453-462.

Pharmacological and toxicological effects of cardiac glycosides (ouabain, digoxin) and the L-type Ca2+ channel antagonist nifedipine on iCell Cardiomyocytes were measured by multielectrode array (MEA). The observed changes in field potential duration and Ca2+ wave amplitude correlated with the compounds’ effects on QT interval and contractility in guinea pig Langendorff hearts. These data demonstrate that iCell Cardiomyocytes area suitable in vitro model for cardioactive ion channel and transporter modulators.

Xu X, Lei Y, et al.
(2013 Mar)

Stem Cell Res. 10(2):213-227.

Prevention of β-Amyloid Induced Toxicity in Human iPS Cell-derived Neurons by Inhibition of Cyclin-dependent Kinases and Associated Cell Cycle Events.

Demonstration of the first known use of human iPS cell-derived neurons (iCell Neurons) to model Alzheimer’s disease through Aβ toxicity, showing potential for use in high throughput drug screening. Several hundred compounds from a GSK proprietary compounds library were screened. Nineteen compounds were selected as hits based on the selection criteria; one of them was a Cdk2 inhibitor, confirming the reliability and sensitivity of GSK’s screening platform based on human iPS cell-derived neurons.

Yu X, Seitz S, et al.
(2012 Dec)

Journal of Neuro.Virology
December 2012

Varicella zoster virus infection of highly pure terminally differentiated human neurons

Development of an in vitro model of varicella zoster virus infection in which highly pure (>95 %) terminally differentiated human neurons derived from pluripotent stem cells were infected with VZV.

Haythornthwaite A, Stoelzle A, et al.
(2012 Aug 24)

J. Biomol. Screen.
17(9):1264-1272.

Characterizing Human Ion Channels in Induced Pluripotent Stem Cell-derived Neurons.

Characterization study demonstrating that iCell Neurons display cellular electrophysiological properties similar to human neurons using manual and automated patch clamp recordings.

Chai X, Dage JL, et al.
(2012 Jun 2)

Neurobiol. Dis.
48(3):356-366.

Constitutive Secretion of Tau Protein by an Unconventional Mechanism.

Demonstration that iCell Neurons release a small percentage of intracellular tau by a nonconventional secretion pathway at comparable levels occurring under physiological conditions in vivo. To study this mechanism, a system is needed to eliminate confounding cell death and have enough signal to detect very small amounts of tau secreted. iCell Neurons enable the study of this mechanism, overcoming the limitations of assay sensitivity seen in primary neurons in intact animals.

Whitemarsh RC, Strathman MJ, et al.
(2012 Jan 5)

Toxicol. Sci.
126(2):426-35.

Novel Application of Human Neurons Derived from Induced Pluripotent Stem Cells for Highly Sensitive Botulinum Neurotoxin Detection.

Evaluation of iCell Neurons as a novel, species relevant model system for Clostridium botulinum neurotoxin (BoNT) detection and mechanistic studies. Compared with primary rat spinal cord cells, iCell Neurons showed equal or increased sensitivity, a steeper dose-response curve and a more complete SNARE protein target cleavage. These data suggest that iCell Neurons provide an ideal and highly sensitive platform for BoNT potency determination neutralizing antibody detection and for mechanistic studies.

Phillips MJ, Wallace KA, et al.
( 2012 Apr)

Inv Opthamology and Visual Sci
53(4):2007-2019.

Blood-derived Human iPS Cells Generate Optic Vesicle-like Structures with the Capacity to Form Retinal Laminae and Develop Synapses.

Use of human blood-derived iPS cells to generate optical vesicle-like structures that have the capacity to self-assembly into rudimentary neuroretinal structures that express markers indicative of chemical and electrical synapses. This study demonstrates the creation of a novel and highly convenient donor cell source for iPS cell-based retinal studies.

Mack AA, Kroboth S, et al.
(2011 Nov 22)

PLoS ONE
6(11):e27956.

Generation of Induced Pluripotent Stem Cells from CD34+ Cells across Blood Drawn from Multiple Donors with Non-Integrating Episomal Vectors.

Demonstration of reprogramming from a single vial of blood or less using cells expressing the early lineage marker CD34 as well as from unpurified peripheral blood mononuclear cells.

Ma J, Guo L, et al.
(2011 Sep 2)

Am J Physiol Heart Circ Physiol.
301(5):H2006-17

High Purity Human-induced Pluripotent Stem Cell-derived Cardiomyocytes: Electrophysiological Properties of Action Potentials and Ionic Currents.

Performance of detailed electrophysiological characterization of highly pure hiPSC-derived cardiomyocytes. Action potentials (APs) were recorded from spontaneously beating cardiomyocytes using a perforated patch method and had atrial-, nodal-, and ventricular-like properties.

Rajesh D, Dickerson S, et al.
(2011 Jun 27)

Blood
118(7):1797-1800

Human Lymphoblastoid B Cell Lines Reprogrammed to EBV-free Induced Pluripotent Stem Cells.

Generation of iPSCs from two LCLs via a feeder-free episomal method using a cocktail of transcription factors and small molecules. LCL-derived iPSCs exhibited normal karyotype, expressed pluripotency markers, lost oriP/EBNA-1 episomal vectors, generated teratomas, retained donor identity and differentiatedin vitro into hematopoietic, cardiac, neural, and hepatocyte-like lineages.

Anson BD, Kolaja KL, and
Kamp TJ.
(2011 Jan)

Clinical Pharmacology & Therapeutics 89(5):754-758.

Opportunities for Use of Human iPS Cells in Predictive Toxicology.

Description of the properties of human induced pluripotent stem (iPS) cells that make them a promising source for toxicity assessment, highlight the progress to date, and point out the important roadblocks that remain.

iPS Cells

References

Notes

Phillips MJ, Wallace KA, et al.
(2012 Apr)

Ophthalmol Vis Sci
53(4):2007-2019.

Blood-derived Human iPS Cells Generate Optic Vesicle-like Structures with the Capacity to Form Retinal Laminae and Develop Synapses.

Demonstrated that human blood-derived iPSCs can generate retinal cell types and that cultured TiPSC-OVs have the capacity to self-assemble into rudimentary neuroretinal structures and express markers indicative of chemical and electrical synapses.

Meyer JS, Howden SE, et al.
(2011 Aug)

Stem Cells
29:1206–1218.

Optic Vesicle Structures Derived from Human Pluripotent Stem Cells Facilitate a Customized Approach to Retinal Disease Treatment.

Demonstration that three-dimensional populations of retinal progenitor cells (RPCs) can be isolated from early forebrain populations in both human embryonic stem cell and hiPSC cultures, providing a valuable tool for developmental, functional, and translational studies. Using the established protocol, a transient population of optic vesicle (OV)-like structures that arose during a time period appropriate for normal human retinogenesis were identified.

Chen G, Gulbranson DR, et al.
(2011 Apr 10)

Nat Methods 8(5):424–429.

Chemically Defined Conditions for Human iPS Cell Derivation and Culture.

Use of new medium (E8) and vitronectin-coated surfaces to demonstrate improved derivation efficiencies of vector-free human iPS cells with an episomal approach.

Howden SE, Gore A, et al.
(2011 Apr 4)

Proc Natl Acad Sci USA
108(16):6537-6542.

Genetic Correction and Analysis of Induced Pluripotent Stem Cells from a Patient with Gyrate Atrophy.

Isolation of iPS cells free of transgene sequences from a patient with gyrate atrophy caused by a point mutation in the gene encoding ornithine-δ-aminotransferase
(OAT) and use of homologous recombination to correct the genetic defect.

Yu J, Chau FK, et al.
(2011 Mar 1)

PLoS ONE
6(3):e17557.

Efficient Feeder-Free Episomal Reprogramming with Small Molecules.

Establishment of a feeder-free reprogramming condition using chemically defined medium with bFGF and N2B27 supplements and chemically defined human ESC medium mTeSR1 for the derivation of footprint-free human iPSCs.

Hu K, Yu J, et al.
(2011 Feb 4)

Blood
117:14e109-e119.

Efficient Generation of Transgene-free Induced Pluripotent Stem Cells from Normal and Neoplastic Bone Marrow and Cord Blood Mononuclear Cells.

Demonstrated that iPSCs free of transgene and vector sequences could be efficiently generated from human bone marrow (BM) and cord blood (CB) mononuclear cells using non-integrating episomal vectors.

Brown ME, Rondon E, et al.
(2010 Jun 29)

PLoS ONE
5(6): e11373.

Derivation of Induced Pluripotent Stem Cells from Human Peripheral Blood T Lymphocytes.

Generation of T lymphocyte-derived iPSCs from small, clinically advantageous volumes of non-mobilized peripheral blood. These T-cell derived iPSCs retain a normal karyotype and genetic identity to the donor.

Yu J and Thomson JA
(2009)

Essentials of Stem Cell Biology, 2nd edition. Elsevier Academic Press.

Induced Pluripotent Stem Cell Derivation.

Description of basic biology/mechanisms, early development, ectoderm, mesoderm, endoderm, methods to application of stem cells to specific human diseases, regulation and ethics, and patient perspectives, and more in the field of stem cells.

Yu J, Hu K, et al.
(2009 Mar 26)

Science
324(5928):797-801.

Human Induced Pluripotent Stem Cells Free of Vector and Transgene Sequences.

Derivation of human iPS cells with the use of nonintegrating episomal vectors.

Ebert AD, Yu J, et al.
(2008 Dec 21)

Nature
457(7227):277-80.

Induced Pluripotent Stem Cells from a Spinal Muscular Atrophy Patient.

Generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy.

Yu J and Thomson JA
(2008 Aug 1).

Genes Dev
22(15):1987-97.

Pluripotent Stem Cell Lines.

Review of the family of pluripotent cell lines derived from early embryos and from germ cells, comparing them with more recently described induced pluripotent stem cells.

Yu J, Vodyanik MA, et al.
(2007 Nov 20)

Science
318(5858):1917-20.

Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells.

Showing that four factors (OCT4, SOX2, NANOG, and LIN28) are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem cells.

Yu J, Vodyanik MA, et al.
(2005 Oct 6)

Stem Cells
24(1):168-76.

Human Embryonic Stem Cells Reprogram Myeloid Precursors Following Cell-Cell Fusion.

Reprogramming of the nuclei of hESC-derived myeloid precursors following cell-cell fusion.

Hematopoietic Cells

Dias J, Gumenyuk M, et al.
(2011 May 11)

Stem Cells Dev.
20(9):1639-47.

Generation of Red Blood Cells from Human Induced Pluripotent Stem Cells.

Description of an approach for the efficient generation of RBCs from hiPSC/hESCs using an OP9 coculture system to induce hematopoietic differentiation followed by selective expansion of erythroid cells in serum-free media with erythropoiesis-supporting cytokines.

Slukvin II and Vodyanik M
(2011 May 1)

Cell Cycle
10(9):1370-3.

Endothelial Origin of Mesenchymal Stem Cells.

Demonstrating that mesodermal MSCs arise from APLNR+ precursors with angiogenic potential, mesenchymoangioblasts.