Human stem cell toxicology 1st Edition by James Sherley ISBN 1782626787 9781782626787

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ISBN 10: 1782626787
ISBN 13: 9781782626787
Author: James Sherley

Human stem cell toxicology 1st Table of contents:

Chapter 1 Addressing Challenges to Progress in Human Stem Cell Toxicology Concepts and Practice

1.1 Filling in the Stem Cell Gap in Human Toxicology

1.2 Historical Impact of the Hierarchical, Anatomical, Sub-disciplinary Structure of Toxicological S

1.3 Human Stem Cell Toxicology as a Stem Cell Exact Science

1.4 Health and Medical Applications for Human Stem Cell Toxicological Sciences

1.5 Introducing the Future Diverse Impacts of Human Stem Cell Toxicology

Acknowledgments

References

Chapter 2 Alternative Methods in Haematopoietic Stem Cell Toxicology

2.1 Introduction

2.2 Haematopoietic Stem Cell Toxicity or Hematotoxicity

2.2.1 Sources of Haematopoietic Stem Cell Toxicity

2.2.2 Importance of Studying Haematopoietic Stem Cell Toxicity

2.2.3 Haematopoietic Stem Cell Toxicity in Drug Development

2.3 Colonogenic Assays as Predictors of Haematopoietic Stem Cell Toxicity

2.3.1 CFU-GM Colonogenic Assay

2.3.2 CFU-Mk Colonogenic Assay

2.3.3 BFU-E Colonogenic Assay

2.3.4 Lymphoid Lineage Based Colonogenic Assays

2.4 Conclusions

Acknowledgments

References

Chapter 3 High-throughput Screening of Toxic Chemicals on Neural Stem Cells

3.1 Neural Stem Cells

3.2 Toxic Chemicals in the Environment

3.3 Mechanisms of Neural Stem Cell Toxicity

3.3.1 Ion Channel Blocking

3.3.2 Drug Metabolism Effects

3.3.3 Oxidative Stress

3.3.4 DNA/RNA Denaturation

3.3.5 Membrane Compromise

3.3.6 Other Mechanisms of Neurotoxicity

3.4 NSC Differentiation

3.5 Conventional In vitro Assays for Toxicity Screening against Neural Stem Cells

3.5.1 Well Plate Assays

3.5.2 Cellular Microarray Assays

3.5.3 Microfluidic Assays

3.5.4 Other Assays

3.6 Challenges of Conventional In vitro Approaches in Neurotoxicity Screening

3.7 Conclusions and Future Directions

Acknowledgments

References

Chapter 4 The Role of Catecholamines in Stem Cell Mobilisation

4.1 Introduction

4.2 Catecholamines

4.3 Catecholamines and Stem Cell Mobilisation

4.3.1 Endothelial Progenitor Cells

4.3.2 Mesenchymal Stem Cells

4.3.3 Catecholamines and Stem Cell Biology

4.4 Consequences of Catecholamine-modulating Agents for Stem Cell Toxicity

4.4.1 Other Considerations

4.5 Concluding Comments

References

Chapter 5 Toxicological Risk Assessment – Proposed Assay Platform Using Stem and Progenitor Cell D

5.1 Introduction

5.1.1 Toxicity

5.1.2 Environmental Toxicology

5.1.3 Predictive Toxicology

5.1.4 Automated High Content Imaging and High Throughput, or High Content, Screening

5.1.5 Risk Assessment

5.1.6 Components of Risk Assessment

5.2 Environmental Toxicological Risk Assessment Employing an Assay Platform That Uses Stem and Proge

5.2.1 Endothelial Colony Forming Cells (ECFCs)

5.2.2 ECFCs are Sensitive to Low-dose Ionizing Radiation (LDIR)

5.2.3 Individual ECFC Cultures Exhibit Donor-related LDIR Responses

5.2.4 The Profiling of Intracellular Signal Transduction Pathways Provides an Insight into the Mecha

5.3 Current State of ECF Platform Development

5.3.1 Impedance-based Analysis of ECFC Viability after Exposure to Environmental Toxicants

5.3.2 ECFCs Exhibit Lot-to-lot Variability in Toxicant Response

5.3.3 Development of a Novel ROS Assay Using ECFCs

5.3.4 Density-dependent ROS Levels in Cultured ECFCs

5.3.5 Signal Transduction Assays in Toxicant-treated ECFCs

5.4 Bioanalytical Method Validation

5.4.1 Development of a Quantitative High Content Imaging (QHCA) Platform Using ECFCs

5.4.2 Optimize Culture Conditions for High-throughput Screening

5.4.3 Initiate Translation of Assay to 384-Well Plates

5.4.4 Incorporation of Automation to Increase Throughput

5.4.5 Validation of the ECFC QHCA

5.4.6 Determining the Z’ factor of the Cell Death Assays Using Positive and Negative Controls

5.4.7 Assessing Sources of Assay Variability Including Manual Pipetting, Plating and Edge Effects

5.4.8 Determining Day-to-day Variability of EC50 for Each Assay

5.4.9 Determining Significant Biological Replicate Power

5.4.10 Perform the High-throughput Assay Using Compounds from the ToxCastTM Phase I Library

5.4.11 Incorporation of the Toxicant-induced ECFC Differentiation Assays into the QHCA Screen

5.4.12 Establish a Repository of ECFCs from Various Donors

5.5 Final Thoughts

References

Chapter 6 Current Developments in the Use of Human Stem Cell Derived Cardiomyocytes to Examine Drug-

6.1 Introduction

6.2 Constraints Due to Species Differences

6.3 Stem Cells and iPSC-CMs

6.4 Limitations with Stem Cells

6.5 Stem Cells in Cardiovascular Safety Pharmacology

6.6 Disease Models Based on iPSC-CMs

6.7 Generation of iPSC-CMs – Considerations on Differentiation, Maturity, Heterogeneity and Purifi

6.7.1 Differentiation

6.7.2 Maturity

6.7.3 Heterogeneity

6.7.4 Purification

6.8 Use of iPSC-CMs in Phenotypic Assays

6.9 Assay Technologies Incorporating iPSC-CMs and hESC-CMs

6.9.1 Manual Patch Clamp

6.9.2 Automated Patch Clamp

6.9.3 MEA (Microelectrode Array)

6.10 CiPA: Comprehensive In vitro Proarrhythmia Assay

6.11 Conclusion

References

Chapter 7 Pesticides and Hematopoietic Stem Cells

7.1 Pesticide Toxicity-induced Disorders of Hematopoietic System

7.1.1 Hematopoietic System and Hematotoxic Pesticides

7.1.2 Pesticide-induced Aplastic Anemia: A Rare but Severe Hematopathology due to Stem Cell Failure

7.1.3 Assessment of Hematotoxicity

7.2 Pesticide Toxicity on Hematopoietic Stem Cells and their Microenvironment

7.2.1 Oxidative Stress Induction

7.2.2 Apoptosis Induction

7.2.3 Alteration of Developmental Signaling Pathways

7.3 Experimental Medicine Against Pesticide Toxicity-induced Hematopoietic Failure

7.4 Future Direction

References

Chapter 8 Epigenetic Impact of Stem Cell Toxicants

8.1 Introduction

8.2 Epigenetic Regulation of Stem Cells

8.3 Stem Cell Toxicants as Modulators of Epigenetic Programming

8.3.1 Heavy Metals

8.3.2 Pharmaceuticals

8.4 Conclusion

Acknowledgments

References

Chapter 9 Metakaryotic Cancer Stem Cells are Constitutively Resistant to X-Rays and Chemotherapeutic

9.1 Introduction

9.1.1 Introduction to Metakaryotic Biology

9.2 Materials and Methods

9.2.1 Methods for Studies of Metakaryotic Cancer Stem Cells In vivo and In vitro

9.3 Results

9.3.1 Observations in Tumors after Radiation Therapy and Chemotherapy

9.3.2 Observations in Cell Cultures

9.4 Discussion

9.4.1 Stem Cells in Human Tumors and Tumor-derived Cell Lines are Amitotic, Metakaryotic Cells

9.4.2 Assays that Recognize and Measure the Toxicity of Radiation and Chemicals to Metakaryotic Stem

9.4.3 Growth and Development of Turnover Units in HT-29 Cultures

9.4.4 Metakaryotic Stem Cells are Resistant to Doses of X-Rays and Drug Classes Commonly in Use for

9.4.5 Metakaryotic Stem Cells are Sensitive to Many Drugs in Common Use: Verapamil, Metformin, NSAID

9.4.6 Hypotheses about Metakaryocidal Mechanisms, e.g. Inhibition of Mitochondrial Function

9.4.7 Other Potential Targets for Metakaryocides: Genome Replication and Segregation

9.4.8 Translation into Clinical Practice

9.4.9 Potential Use of Metakaryocides in Prevention of Cancers and Other Clonal Diseases

9.4.10 Other Considerations

Acknowledgments

References

Chapter 10 Distributed Stem Cell Kinetotoxicity: A New Concept to Account for the Human Carcinogenic

10.1 Introduction

10.2 Results and Discussion

10.2.1 Development of a High-throughput Cell Kinetics Assay for Kinetotoxicity

10.2.2 Use of High-throughput Screening to Detect Benzene and Hydroquinone as Kinetotoxic Agents

10.2.3 Confirmation Studies for Benzene and Hydroquinone Kinetotoxicity

10.2.4 Validation of Benzene and Hydroquinone Kinetotoxicity with DSCs

10.2.5 Use of Microarray Analyses to Discover a Potential Molecular Biomarker for Kinetotoxicity

10.3 Conclusions and Closing Thoughts

10.3.1 Kinetotoxicity, An Extended Concept in Human Stem Cell Toxicology for Carcinogens

10.3.2 Development of a High-throughput Screen for Kinetotoxic Agents

10.3.3 Mechanisms of Kinetotoxicity by Benzene and Hydroquinone

10.3.4 The DSC Specification Problem in Human Stem Cell Toxicology

10.3.5 Looking Forward

10.4 Materials and Methods

10.4.1 Cells

10.4.2 Chemicals

10.4.3 Development of the High-throughput Microplate Assay for Kinetotoxicity

10.4.4 Assays for Self-renewal Kinetics Pattern Determination

10.4.5 Microarray Analyses

Acknowledgments

References

Chapter 11 Cancer Stem Cells as Therapeutic Targets

11.1 Introduction

11.2 CSC Markers and Therapeutic Targets

11.3 Signal Transduction in CSCs and Targeted Agents

11.4 Asymmetric Cell Divisions: The Dilemma of Studies on CSCs

11.5 Asymmetric Cell Divisions: Visualization of CSCs and Toxicology

11.6 Asymmetric Cell Divisions; Potential Therapeutics Targeting CSCs

11.7 Closing Remarks

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