Approximately 6,500 toxicologists from more than 50 countries are expected to share their research and expertise during the 160+ Scientific Sessions, featuring nearly 2,500 abstracts. This makes the SOT Annual Meeting an ideal place to expand your scientific knowledge, find new collaborators, and catch up on the latest techniques and initiatives.
Visit Cellular Dynamics at booth 1627 and learn about our recently launched iCell® GlutaNeurons – a human excitatory neuronal model.
Wednesday, March 15 12:00 – 1:00 pm | Room 337
Squeezing More Out of iPSC-derived Cardiomyocytes: Providing Better Solutions through Increased Functionality and Integrative Analyses
Presented by: ACEA Biosciences, Cellular Dynamics International and Charles River Labs
Abstract: This forum showcases practical advances in xCELLigence® CardioECR and iPSC-cardiomyocyte-based solutions for toxicity studies. Specifically, data will be presented illustrating increased cardiomyocyte functionality and how integrating electrical and mechanical responses provides mechanistic and translatable results from a variety of chemical classes including small molecule kinase inhibitors and inotropic compounds.
Wednesday, March 15 | 1:30 – 2:30 pm | Room 338
iPSC-derived Glutamatergic Neurons: Something to Get Excited About!
Presented by: Cellular Dynamics International and Cyprotex
Abstract: iCell® GlutaNeurons are human excitatory neurons that form spontaneously bursting networks modulated by pro-convulsant and neuroactive molecules, thus adding a new dimension to the toxicologist’s toolbox. This workshop will illustrate the attributes of these neurons, provide case studies highlighting their use, and illustrate potential analyses for pro-seizurogenic investigations.
Monday, March 13
Poster Number 1263 | Poster Board P423 | Exhibit Hall
Presentation: 9:30 am – 12:45 pm
Session: Liver: In Vitro and In Silico Approaches
3D and 2D In Vitro Models of Xenobiotic Induced Hepatotoxicity for Short and Long Term Exposure Studies Using iCell Hepatocytes 2.0
Presenting Author: Tromondae Feaster, Cellular Dynamics International
Abstract: Hepatotoxicity is a leading cause of drug withdrawal from the market, and current preclinical models are not sufficiently predictive of drug effects in humans. Causes of hepatotoxicity include intrinsic toxic effects and the enzymatic production of toxic metabolites. Development of more predictive in vitro model systems to identify hepatotoxicity early in drug development is critical for decision making and to avoid Drug Induced Liver Injury (DILI) in the clinic. Moreover, batch to batch and donor inconsistencies in primary human hepatocytes, as well as lack of maintained metabolic function have resulted in conflicting reports and poor predicticity. Human induced pluripotent stem cell (iPSC)-derived hepatocytes (iCell® Hepatocytes 2.0) that exhibit high purity and sustained biologically relevant functions help to address some of the needs of hepatotoxicity assessment. Here, we set out to demonstrate the functional utility of iCell Hepatocytes 2.0 (HC 2.0) to assess acute and chronic drug-induced hepatotoxicity. We evaluated HC 2.0 responses to a set of known hepatotoxins (i.e., amiodarone, acetaminophen (APAP), troglitazone, nefazadone, chlorpromazine, and FCCP) across a number of cell death readouts highlighting their capacity for mechanistic toxicity studies. In addition, the prolonged viability also enables chronic dosing in vitro affording the potential to detect the effects of slow to form metabolites and also perform analyses at physiologically relevant concentrations over protracted exposure periods. The short term high concentration sensitivities observed were comparable to those seen with primary human hepatocytes. However, effects seen over 48 hr and 7 day dosing are illustrative of the potential of HC 2.0 for predictive in vivo/in vitro toxicity correlation. With the ability to routinely access patient specific genotypes and also culture in 3D spheroids and in co-culture with other hepatic stellate cells HC 2.0 provide a biologically relevant human model system for investigating hepatotoxicity in preclinical drug development. These data illustrate how human-based iCell products offer an excellent model system for assessing compound effects in human-derived hepatocytes. In total, iPSC technology enables a reliable and predictive model systems not previously attainable, and provides new solutions, tools, and opportunities for more predictive toxicity testing.
Tuesday, March 14
Poster Number 1727 | Poster Board P212 | Exhibit Hall
Presentation: 9:30 am – 12:45 pm
Session: Neurotoxicology: General Neurotoxicity
Human iPSC Derived Neurons Provide Relevant Mechanistic Insight into Neurotoxicity
Presenting Author: Blake Anson, Cellular Dynamics International
Abstract: Human cell types differentiated from induced pluripotent stem cells (iPSC) offer a unique access to human cellular material for toxicity screening. Such access is especially valuable for tissues such as those of neuronal origin that have been traditionally impossible to obtain. An additional key advantage to iPSC systems is contextual relevance for mechanistic studies that overcome many limitations of rodent primary cells and immortalized cell lines. Here we provide examples of using iPSC-derived cortical GABAergic, glutamatergic, and midbrain dopaminergic neurons in image-based screens for developmental and environmental neurotoxicants. Interrogations focus on unique neuronal activity including neurite outgrowth, Ca2+ oscillations, and excitotoxicity. The utility of the various models is demonstrated by; 1) sub-type specific behavior 2) differential responses to toxicants, and 3) multiplexing experiments to move from phenotypic to mechanistic interpretations. The highly-excitatory iPSC-glutamatergic neurons display synchronized network-level bursting behaviors on the MEA, while cortical GABAergic neurons also display electrical activity but lack network synchronization. iPSC-neurons are susceptible to neurotoxicants with both the broad-spectrum kinase inhibitor staurosporine as well as glutamate inducing cell death. The effects of glutamate are inhibited by the antagonists DNQX and D-AP5 indicating excitotoxicity as the underlying mechanism for glutamate. Further, multiplexed experiments enable easy movement from phenotypic responses such as LDH release and ATP production to specific aspects of cell death such as apoptosis via caspase activation. Overall, iPSC-derived neurons exhibit functional glutamate pathways that respond appropriately to known agonists and antagonists, thus providing biologically relevant models for identifying emerging targets for neuro-based toxicity research and beyond.
Thursday, March 16
Poster Number 3226 | Poster Board P186 | Hall A
Presentation: 8:30 – 11:45 am
Session: Emerging Technologies
Excitatory Pharmacology Induces Seizurogenic Phenotypes in iPSC Derived Neuronal Cultures In Vitro
Presenting Author: Kile Mangan, Cellular Dynamics International
Abstract: 65 million individuals suffer from epilepsy and one-third of them live with uncontrollable seizures because no known effective treatments are available. Epilepsy is a disturbance in the electrical activity of the brain manifested via countless etiologies including genetic origins, head trauma, stroke, metabolic disturbances, and in some cases, prescription medications. Some ‘regular’ prescription medications, which treat blood pressure or cholesterol levels, bladder infections, pain, sleep, weight loss, as well as medications for ADHD, psychiatric disorders, Parkinson’s Disease and other dementias, are on occasion, known to display seizurogenic potential. Furthermore, and unfortunately, the likelihood of being diagnosed with epilepsy after suffering just one ‘first time seizure’ is roughly 50%. It is crucial for prescription medications to first be screened for any ‘seizurogenic potential’ before being openly offered to the general public. Central to this vision is induced pluripotent stem cell (iPSC) technology, which provides a human cell-based platform to expand our understanding of how pharmacology affects the human condition. We have produced human neuronal populations from iPSC that, when combined with micro-electrode array (MEA) technology, advances and provides unparalleled investigation into how pharmacology affects human neuron-networked activity. Excitatory populations of iPSC-derived cortical neurons (e.g. iCell GlutaNeurons) develop and display network-level coordinated neuronal activity in vitro, evident by synchronized bursts captured and measured via MEA. Assay optimization dictates best practice timelines for ‘seizurogenic potential’ screening occurs between DIV20-23, post-thaw. Excitatory pharmacology that displays dose-dependent seizurogenic-effects include picrotoxin [0.3-100 µM], GABAzine [1-100 µM], bicuculline [4-400 µM], pentylenetetrazol [7 µM-2 mM], 4-aminopyridine [1.6-50 µM], and kainic acid [0.4-300 µM]. Activity metrics displaying dose-dependent changes with pharmacology include: mean firing rate, ‘single-channel’ burst rate, intensity and duration, ‘network-level’ burst rate, intensity and duration, and synchrony measures. The presented data illustrate and marry the “seizure-in-a-dish” technology, previously limited to rodent-only investigation, with human iPSC-technology to create an unprecedented investigatory space for drug screening.
Poster Number 3223 | Poster Board P183 | Hall A
Presentation: 8:30 – 11:45 am
Session: Emerging Technologies
Diversity in a Dish: A Population Based Organotypic Human In Vitro Model for Cardiotoxicity Testing
Presenting Author: Fabian Grimm, Texas A&M University
Abstract: The implementation of organotypic culture models in human health safety assessments is impeded by the lack of multidimensional high-throughput testing strategies that are amenable for (1) providing chemical-specific uncertainty factors for estimation of inter-individual susceptibilities to adverse chemical effects and (2) for extrapolation of in vitro-derived dose-response relationships to physiologically-relevant exposure levels. We previously demonstrated the feasibility of combinatorial in vitro/ in silico screening approaches for functional and mechanistic cardiotoxicity profiling in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, thereby prompting the hypothesis that a population-based in vitro cardiotoxicity model is a viable option for translatable chemical hazard assessment that is amenable for data-integrative in vitro-to-human in vivo extrapolation. Thus, we exposed cardiomyocytes derived from 30 “healthy” donors to more than 100 chemicals representing a broad range of toxicologically relevant compound classes, i.e. drugs and environmental chemicals, including pharmaceuticals with known human cardiophysiological concentration-response profiles, allowing either direct extrapolation or model-derived prediction of human cardiotoxic effects. Cells were exposed to test chemicals in concentration-response covering nanomolar and micromolar concentration ranges, selected to be representative of human Cmax range (where available) for 90 min and 24 hrs. Kinetic Ca2+ flux measurements and high-content live cell imaging revealed chemical class-specific effects on cardiomyocyte contractility and cellular/ mitochondrial toxicity. Interestingly, observed variation in chemical responses was indicative of biologically-relevant, donor-specific variabilities and reflective of donor-cell associated differences in cardiophysiologic performance in untreated iPSC cardiomyocytes. Altogether, this work is pioneering the “diversity in a dish” concept through the use of organotypic cell culture models for human health safety assessments.