A comprehensive and authoritative compilation of up-to-date developments in stem cell research and its use in toxicology and medicine Presented by internationally recognized investigators in this exciting field of scientific research Provides an insight into the current trends and future directions of research in this rapidly developing new field A valuable and excellent source of authoritative and up-to-date information for researchers, toxicologists, drug industry, risk assessors and regulators in academia, industry and government

Drug discovery and development requires preclinical models to eliminate flawed compounds from development pipelines. Unfortunately, current models have limitations, occasionally resulting in toxic or ineffective compounds progressing to the clinic at great cost and patient risk. Utilising stem cell technology, it is now possible to generate sophisticated models with human biology and physiological context, potentially overcoming the limitations of more established preclinical models. In this thesis I have investigated the use of embryonic stem cell derived cardiac cells for use as models in pharmacology, physiology and toxicology studies. Mouse embryonic stem cells were differentiated to generate cardiomyocytes in multicellular aggregates containing not only myocytes, but also pacemaker cells, fibroblasts and endothelium. These aggregates were used for pharmacology studies, where the signaling resulting from [beta]-adrenoceptor and adenosine receptor stimulation was explored. Using the same differentiation method, in combination with a pan-cardiac reporter for cell enrichment, the function of individual cardiac cells was measured using calcium imaging. Following extensive method development, multiple phenotypes were identified in the enriched population based on spontaneous calcium oscillations. These distinct phenotypes were characterised based on calcium oscillation kinetics, pharmacology and immunocytochemistry. Using human stem cell derived cardiomyocyte aggregates I studied the effects of doxorubicin (a known cardio-toxin) and Trastuzumab, a humanised antibody with disputed cardio-toxicity. Following extensive method development, toxicity was observed for both doxorubicin and Trastuzumab. Furthermore, mechanistic studies implicate multiple cell types mediating Trastuzumab toxicity via a complicated signaling pathway. Based on my results, as models of pharmacology stem cell derived cardiomyocytes provide access to a physiologically heterogeneous model that may be useful for the screening of compounds for non-specific cardiac activity. Unfortunately, the complexity of multicellular aggregates limits their use in characterizing less established, or complicated receptor signaling pathways. Results from calcium imaging studies indicate that at a single cell level, there is considerable heterogeneity of stem cell derived cardiac cells. Focusing on cells with spontaneous calcium oscillations, presumably pacemaker cells, it may be possible to gain greater insight into the mechanisms required to maintain spontaneous cardiac activity, and identify drugs that disrupt it. The results of the Trastuzumab toxicity study provide evidence of a novel mechanism of Trastuzumab cardio-toxicity. More importantly, these results support the use of stem cell derived models for toxicology screening, particularly of humanised antibodies whose toxicity may be missed in classical models. The work presented in this thesis identified novel pacemaker phenotypes previously unreported, and a novel mechanism for Trastuzumab toxicity. Furthermore, this thesis highlights the strengths and weaknesses of stem cell derived models for use in pharmacology, physiology and toxicology assays.

Stem Cells in Neurotoxicology, Volume Twelve in the Advances in Neurotoxicology series, presents interesting chapters written by an international board of authors. Chapters in this new release include Brain organoids as a translational model of human developmental neurotoxicity, Self-organizing human neuronal cultures in the modeling of environmental impacts on learning and intelligence, Utilization of human stem cell/neural progenitor tests to examine neurotoxic impacts on differentiation, Characterization of neuronal and other cellular sub-types in human stem cell cortical neuron differentiations, Utility of human stem cell models to study persistent neurotoxicity, and Utility of human stem cell models to study chronic neurotoxicity. - Provides the latest information on Neurotoxicology - Offers outstanding and original reviews on Neurotoxicology - Serves as an indispensable reference for researchers and students alike

Toxicity against tissue stem cells (TSCs) is a major problem in drug development and environmental health science. Despite their essential function in all human cellular tissues, the nature of tissue stem cells is not fully understood. The small fraction of stem cells in tissues and the lack of specific biomarkers for their quantification present a formidable challenge to developing tools for their study and assays that can identify stem cell-toxic agents. Human Stem Cell Toxicology reveals TSC toxicity as a biomedical reality that is now well under siege by newly emerging ideas and technologies, despite these challenges. Chapters consider stem cell toxicity by environmental agents, pharmaceutical drug candidates, and marketed therapeutic medicines with adverse side effects. New insights to cellular, molecular, biochemical and chemical mechanisms of human tissue stem cell toxicity are brought together. Experimental and theoretical treatments are of specific topics, including approaches to monitoring TSC function, newly discovered TSC types and TSC toxicity resistance mechanisms are covered by expert authors. This book informs and champions the continued development of innovative technologies to predict the TSC toxicity of compounds before their use, whether in patients or the environment, by addressing emerging new cell-based approaches and concepts for technical innovation. This publication will be a useful reference for postgraduate students and researchers working in toxicology, pharmaceutical science, tissue cell biology and stem cell biology.

This book contains material contributed by forward-looking scientists who work at the interface of stem cell research and applied science with the aim to improve human fetal safety and the understanding of human developmental and degenerative disorders. Provides important platforms and contemporary accounts of the state of stem cell research in the fields of toxicology and teratology Considers both in vitro uses of stem cells as platforms for teratology and also stem cellopathies, which are in vivo developmental and degenerative disorders Helps the pharmaceutical industry and safety and environmental authorities validate the status quo of in vitro toxicity test systems based on human pluripotent stem cells and their derivatives

The volume brings together the once disparate knowledge of cultural techniques and thus provides an important reference work for industrial and academic toxicologists.