Chapter
Chapter 2 Application of Stem Cells and iPS Cells in Toxicology
2.3 Stem Cell (SC) Classification
2.4 Stem Cells and Pharmacotoxicological Screenings
2.5 Industrial Utilization Showcases Stem Cell Technology as a Research Tool
2.6 Multipotent Stem Cells (Adult Stem Cells) Characteristics and Current Uses
2.7 Mesenchymal Stem Cells (Adult Stem Cells)
2.8 Hematopoietic Stem Cells (Adult Stem Cells)
2.12 Use of SC and iPSC in Drug Safety
2.12.1 Potential Benefits of Stem Cell Use in Other Areas
2.12.3 Economic Benefits of Stem Cell Use
2.13 Conclusions and Future Applications
Chapter 3 Stem Cells: A Potential Source for High Throughput Screening in Toxicology
3.2.1 Embryonic Stem Cells (ESCs)
3.2.4 Adult Stem Cells in Other Tissues
3.3 High Throughput Screening (HTS)
3.3.1 Current Strategies and Types of High Throughput Screening
3.3.2 In Vitro Biochemical Assays
3.3.2.1 Fluorescent Based Assays
3.3.2.2 Luminescence‐Based Assays
3.3.2.3 Colorimetric and Chromogenic Assays
3.3.2.4 Mass Spectroscopy (MS) Based Detection Assays
3.3.2.5 Chromatography-Based Assays
3.3.2.6 Immobilization and Label-Free Detection Assays
3.3.3.1 Reporter Gene Assays
3.3.3.2 Cell-Based Label Free Readouts
3.4 Need for a Stem Cell Approach in High Throughput Toxicity Studies
3.5 Role of Stem Cells in High Throughput Screening for Toxicity Prediction
3.5.1 Applications of Stem Cells in Cardiotoxicity HTS
3.5.2 Applications of Stem Cells in Hepatotoxicity HTS
3.5.3 Applications of Stem Cells in Neurotoxicity HTS
Chapter 4 Human Pluripotent Stem Cells for Toxicological Screening
4.2 The Biological Characteristics of hPSCs
4.2.1 The Biological Characteristics of hESCs
4.2.2 The Biological Characteristics of hiPSCs
4.3 Screening of Embryotoxic Effects using hPSCs
4.3.1 Screening of Embryotoxic Effects using hESCs
4.3.2 Screening of Embryotoxic Effects using hiPSCs
4.4 The Potential of hPSC-Derived Neural Lineages in Neurotoxicology
4.4.1 The Challenge of hPSC s-Derived Neural Lineages in Neurotoxicology Applications
4.4.2 The New Biomarkers in Neurotoxicology using hPSC -Derived Neural Lineages
4.4.2.1 Gene Expression Regulation
4.4.2.2 Epigenetic Markers
4.4.2.3 Mitochondrial Function
4.4.3 The New Methods in Neurotoxicology using hPSC -Derived Neural Lineages
4.4.3.1 High-Throughput Methods
4.4.3.2 Three-Dimensional (3-D) Culture
4.5 The Potential of hPSC-Derived Cardiomyocytes in Cardiotoxicity
4.5.1 The Challenge of hPSC-Derived Cardiomyocytes in Cardiotoxicology Applications
4.5.2 The New Biomarkers in Cardiotoxicology using hPSC-Derived Cardiomyocytes
4.5.2.2 Multi-Electrode Array
4.5.3 High-Throughput Methods
4.6 The Potential of hPSC-Derived Hepatocytes in Hepatotoxicity
4.6.1 The Challenge of hPSCs-Derived Hepatocytes in Hepatotoxicology Application
4.6.2 The New Biomarkers in Hepatotoxicology using hPSC -Derived Hepatocytes
4.6.3 The New Methods in Hepatotoxicology using hPSC ‐Derived Hepatocytes
4.6.3.1 iPSC-HH-Based Micropatterned Co-Cultures (iMPCC s) with Murine Embryonic Fibroblasts
4.6.3.2 Suspension Culture of Aggregates of ES Cell-Derived Hepatocytes
4.6.3.3 Long-Term Exposure to Toxic Drugs
4.7 Future Challenges and Perspectives for Embryotoxicity and Developmental Toxicity Studies using hPSCs
Chapter 5 Effects of Culture Conditions on Maturation of Stem Cell‐Derived Cardiomyocytes
5.2 Lengthening Culture Time
5.4 Structured Substrates
Chapter 6 Human Stem Cell-Derived Cardiomyocyte In Vitro Models for Cardiotoxicity Screening
6.1.1 Cardiotoxicity in Preclinical and Clinical Drug Development
6.1.2 Functional Cardiotoxicity
6.1.3 Structural Cardiotoxicity
6.1.4 Requirement for Improved In Vitro Models to Predict Human Cardiotoxicity
6.2 Overview of hPSC‐Derived Cardiomyocytes
6.3 Human PSC-CM Models for Cardiotoxicity Investigations
6.3.1 hPSC-CMs for the Assessment of Electrophysiological Cardiotoxicity
6.3.1.1 Patch Clamp Assays
6.3.1.2 Voltage Sensitive Dyes (VSDs)
6.3.1.4 Multielectrode Array (MEA) Assays
6.3.1.6 Calcium Imaging Assays
6.3.2 hPSC-CMs for the Assessment of Contractile Cardiotoxicity
6.3.2.1 Muscular Thin Films
6.3.2.2 Engineered Heart Tissues (EHTs)
6.3.2.4 Calcium Imaging Assays
6.3.3 hPSC-CMs for the Assessment of Structural Cardiotoxicity
6.3.3.1 Mechanisms of Cardiomyocyte Cell Death as Endpoints in Drug Screening
6.3.3.2 High Content Analysis
6.3.3.4 SeaHorse Flux Analysers
6.3.3.5 Complex and 3D Models
6.4 Conclusions and Future Direction
Chapter 7 Disease-Specific Stem Cell Models for Toxicological Screenings and Drug Development
7.1 Evidence for Stem Cell‐Based Drug Development and Toxicological Screenings in Psychiatric Diseases, Cardiovascular Diseases and Diabetes
7.1.1 Introduction into Stem-Cell Based Drug Development and Toxicological Screenings
7.1.2 Relevance for Psychiatric and Cardiovascular Diseases
7.1.3 Advantages of Human Disease-Specific Stem Cell Models
7.1.4 Pluripotent Stem Cell Models
7.1.5 Reprogramming of Somatic Cells for Disease-Specific Stem Cell Models
7.1.6 Transdifferentation of Somatic Cells for Disease-Specific Stem Cell Models
7.2 Disease-Specific Stem Cell Models for Drug Development in Psychiatric Disorders
7.2.1 Disease-Specific Stem Cell Models Mimicking Neurodegenerative Disorder
7.2.2 Disease-Specific Stem Cell Models Mimicking AD
7.2.3 Disease-Specific Stem Cell Models Mimicking Neurodevelopmental Disorders
7.2.4 Disease-Specific Stem Cell Models Mimicking SCZ
7.3 Stem Cell Models for Cardiotoxicity and Cardiovascular Disorders
7.3.1 Generating Cardiomyocytes In Vitro
7.3.2 Generating Microphysiological Systems to Mimic the Human Heart
7.3.3 Disease-Modeling using Microphysiological Cardiac Systems
7.4 Stem Cell Models for Toxicological Screenings of EDCs
7.4.1 In Vitro Analysis of EDCs in Reproduction and Development
7.4.2 In Vitro Analysis and Toxicological Screenings of Drugs
Chapter 8 Three-Dimensional Culture Systems and Humanized Liver Models Using Hepatic Stem Cells for Enhanced Toxicity Assessment
8.2 Hepatic Cell Lines and Primary Human Hepatocytes
8.3 Embryonic Stem Cells and Induced Pluripotent Stem‐Cell Derived Hepatocytes
8.4 Ex Vivo: Three-Dimensional and Multiple-Cell Culture System
8.5 In Vivo: Humanized Liver Models
Chapter 9 Utilization of In Vitro Neurotoxicity Models in Pre‐Clinical Toxicity Assessment
9.1.1 Limitations of Animal Models and the Utility of In Vitro Assays for Neurotoxicity Testing
9.1.2 How Regulatory Requirements Can Shape the Development of In Vitro Screening Tools and Efforts
9.1.3 In Vitro Assays as Useful Tools for Assessing Neurotoxicity in a Pharmaceutical Industry Setting
9.2 Current Models of Drug‐Related Clinical Neuropathies and Effects on Electrophysiological Function
9.2.1 Neuropathy Assessment
9.2.2 Seizure Potential and Electrophysiological Function Assessments
9.2.3 Multi Electrode Arrays to Model Electrophysiological Changes Upon Drug Treatment
9.3 Cell Types that Can Potentially Be Used for In Vitro Neurotoxicity Assessment in Drug Development
9.3.1 Primary Cells Harvested from Neuronal Tissues
9.3.2 Immortalized Cells and Cell Lines
9.3.3 Induced Pluripotent Stem (iPS) Derived Cells
9.4 Utility of iPSC Derived Neurons in In Vitro Safety Assessment
9.4.1 iPSC Derived Neurons in Electrophysiology
9.4.2 iPSC Derived Neurons to Study Neurite Dynamics
9.5 Summary of Key Points for Consideration in Neurotoxicity Assay Development
Chapter 10 A Human Stem Cell Model for Creating Placental Syncytiotrophoblast, the Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics
10.2 General Features of Placental Structure
10.4 Human Placental Cells in Toxicology Research
10.5 Placental Trophoblast Derived from hESC
10.6 Isolation of Syncytial Areas from BAP‐Treated H1 ESC Colonies
10.7 Developmental Regulation of Genes Encoding Proteins Potentially Involved in Metabolism of Xenobiotics
10.7.1 Cytochrome P450 Family Members
10.7.2 SLC Gene Family Members
10.7.3 ATP-Binding Cassette (ABC) Transporters
10.7.4 Metallothionein Family Members
Chapter 11 The Effects of Endocrine Disruptors on Mesenchymal Stem Cells
11.1 Mesenchymal Stem Cells
11.1.3 Functions and Activities
11.2 Endocrine Disruptors
11.2.1 EDC Major Epidemiologic Associations
11.2.1.1 EDC Association with Obesity
11.2.1.2 EDC Association with Diabetes
11.2.2 Challenges with Exposure Study Interpretation in Human Subjects
11.2.2.1 Nonmonotonicity of EDC Dose‐Response Curves
11.2.2.2 EDC Exposure at Critical Developmental Windows and Association with Adult Disease
11.2.2.3 Effects of Combinations of EDCs
11.2.3 Mechanisms of Action of EDCs
11.3.1.1 Cell-Type Specific Effects
11.3.1.2 Molecular Effects
11.3.2.1 Cell-Specific Effects
11.3.2.2 Molecular Effects
11.4 Alkyl Phenols and Derivatives
11.4.1 Cell-Specific Effects
11.4.1.1 Effects on Adipocytes and Precursors of Adipocytes
11.4.1.2 Effects on Osteoblasts and Precursors of Osteoblasts
11.5.1 Cell-Specific Effects
11.5.1.1 Effects on Adipocytes and Precursors of Adipocytes
11.5.1.2 Effects on Osteoblasts and Precursors of Osteoblasts
11.6 Polychlorinated Biphenyls
11.6.1 Cell-Specific Effects
11.6.1.1 Effects on Adipocytes and Precursors of Adipocytes
11.6.1.2 Effects on Osteoblasts and Precursors of Osteoblasts
11.7.1 Cell-Specific Effects
11.7.1.1 Effects on Adipocytes and Precursors of Adipocytes
11.7.1.2 Effects on Osteoblasts and Precursors of Osteoblasts
11.8 Areas for Future Research
Chapter 12 Epigenetic Landscape in Embryonic Stem Cells
12.2 DNA Methylation in ESCs
12.3 Histone Methylation in ESCs
12.4 Chromatin Remodeling and ESCs Regulation
Chapter 13 The Effect of Human Pluripotent Stem Cell Platforms on Preclinical Drug Development
13.2 Core Signaling Pathways Underlying hPSC Stemness and Differentiation
13.3 Basic Components of In Vitro and Ex Vivo hPSC Platforms
13.3.1 Growth Medium Development for Drug Discovery
13.3.2 Choices of Extracellular Components
13.4 Diverse hPSC Culture Platforms for Drug Discovery
13.4.1 Colony Type Culture-Based Modules
13.4.2 Suspension Culture
13.4.3 Non-Colony Type Monolayer Empowers Efficient Drug Screening
13.4.4 Tissue Integration: Morphogenesis and Organogenesis
13.5 Representative Analyses of hPSC‐Based Drug Discovery
13.5.1 Neuroectodermal Disease Models for Drug Assessment
13.5.2 Hepatic Models for Drug Assessment
13.5.3 Cardiomyocytes for Cancer Drug Discovery
13.6 Current Challenges and Future Considerations
13.6.1 Dimensionality, Maturity, and Functionality of Differentiated Cells
13.6.2 Complexity: Genetics versus Epigenetics
13.6.3 Other Notable Factors
Chapter 14 Generation and Application of 3D Culture Systems in Human Drug Discovery and Medicine
14.2 Traditional Scaffold-Based Tissue Engineering
14.2.1 Materials for Fabrication of Scaffolds
14.2.1.1 Naturally Occurring Polymers
14.2.1.2 Biodegradable Synthetic Polymers
14.2.1.3 Bioactive Glass and Glass Ceramics
14.2.2 Fabrication Methods
14.2.2.1 Photolithography
14.2.2.2 Soft Lithography
14.3 Scaffold-Free 3D Culture Systems
14.4 Modular Biofabrication
14.5.1 Bioprinting Strategies
14.5.1.1 Microextrusion Bioprinting Technology
14.5.1.2 Inkjet Bioprinting Technology
14.5.1.3 Laser-Assisted Bioprinting Technology
14.6 Tissue Modelling and Regenerative Medicine Applications of Pluripotent Stem Cells
14.6.1 The In Vitro Hepatic Models
14.7 Applications in Drug Discovery and Toxicity
14.7.1 3D Culture Systems
14.7.2 Liver In Vitro Models for Drug Discovery, Toxicity, and Modelling Drug Metabolism
Chapter 15 Characterization and Therapeutic Uses of Adult Mesenchymal Stem Cells
15.2 MSC Characterization
15.2.1 MSC Negative Markers
15.2.2 MSC Positive Markers
15.2.3 MSC Self-Renewal and Maintenance
15.2.4 MSCs Proliferate in Hypoxia Faster than in Normoxia
15.2.5 MSCs Kill Bacteria by Autophagy
15.2.6 MSCs Exhibit Mitochondrial Remodeling
15.2.7 MSCs and Signal Transduction
15.3 MSCs and Tissue or Organ Therapy
15.3.1 MSCs Improve Acute Lung Injury
15.3.2 MSCs Improve Renovascular Function in the Kidney
15.3.3 MSCs Effectively Treat Articular Cartilage Defects and Osteoarthritis
15.3.4 Differentiated MSCs Improve Myocardial Performance
15.3.5 MSCs Improve Radiation-Induced Damage in the Intestinal Mucosal Barrier
15.3.6 MSCs Repair Radiation-Induced Liver Injury
15.3.7 MSCs Accelerate Radiation-Induced Delay in Wound Healing
15.3.8 MSCs Improve Radiation-Induced Cognitive Dysfunction
15.3.9 MSCs Improve Survival after Ionizing Radiation Combined Injury
15.3.10 MSCs Attenuate the Severity of Acute Graft-Versus-Host Disease
15.3.11 MSCs Preconditioned with Mood Stabilizers Enhances Therapeutic Efficacy for Stroke and Huntington’s Disease
Chapter 16 Stem Cell Therapeuticsfor Cardiovascular Diseases
16.2 Types of Stem/Progenitor Cell-Derived Endothelial Cells
16.3 EPC and Other Stem/Progenitor Cell Therapy in CVDs
16.3.1 EPC Therapy for Ischemic Vascular Diseases (PAD/HLI)
16.3.2 EPC Therapy for Ischemic Cardiac Diseases (MI)
16.3.3 EPC Therapy in Clinical Trials for CVDs
16.4 Strategies and Approaches for Enhancing EPC Therapy in CVDs
Chapter 17 Stem-Cell-Based Therapies for Vascular Regeneration in Peripheral Artery Diseases
17.1 Sources of Stem Cells for Vascular Regeneration
17.1.2 Umbilical Cord-Blood-Derived Stem Cells
17.1.3 Embryonic Stem Cells
17.1.4 Induced Pluripotent Stem Cells
17.2 Canonic Mechanisms Governing Vascular Stem Cells Therapeutic Potential
17.2.1 Differentiation into Vascular Cells
17.2.2 The Paracrine Effect
17.2.2.1 Pro-Angiogenic Factor
17.2.2.2 Vasoactive Factors
17.2.2.3 Extracellular Membrane Vesicles
17.2.3 Interaction with the Host Tissue
17.3 Stem-Cell-Based Therapies in Patients with Peripheral Artery Disease
17.3.1 Mononuclear Cells from Bone Marrow and Peripheral Blood
17.3.2 Selected Cell Population
17.3.3 Endothelial Progenitor Cells
Chapter 18 Gene Modified Stem/Progenitor-Cell Therapy for Ischemic Stroke
18.2 Gene Modified Stem Cells for Ischemic Stroke
18.2.1 Gene Modified Mesenchymal Stem Cells
18.2.2 Gene Modified Neural Stem Cells
18.2.3 Gene Modified Endothelial Progenitor Cells
18.2.4 Induced Pluripotent Stem Cells
18.3 Gene Transfer Vectors
18.4 Unsolved Issues for Gene‐Modified Stem Cells in Ischemic Stroke
Chapter 19 Role of Stem Cells in the Gastrointestinal Tract and in the Development of Cancer
19.2 GI Development and Regeneration
19.2.2 GI Stem Cells and Liver Regeneration
19.3 GI Tumorigenesis and Stemness Gene Expression
19.4 Toxicants and Other Stress Trigger Epigenetic Changes, Dedifferentiation, and Carcinogenesis
19.5 Summary and Perspective
Chapter 20 Cancer Stem Cells: Concept, Significance, and Management
20.2 Stem Cells and Cancer: Historical Perspective
20.3.1 The Origin of Cancer Stem Cells
20.3.1.1 Genetic Instability and Cell Fusion
20.3.1.2 Horizontal Gene Transfer
20.3.1.3 Microenvironment
20.4 Identification and Isolation of CSCs
20.5 Pathological Significance of Cancer Stem Cells
20.6 Pathways Regulating Cancer Stem Cells
20.7 Therapeutic Strategies Targeting Cancer Stem Cells
20.7.1 Targeting CSC-Specific Markers
20.7.2 Targeting CSC-Specific Molecular Signaling Pathways
20.7.3 CSC-Related Immunotherapy
20.7.4 Targeting CSC Microenvironment
20.8 Conclusion and Future Directions
Chapter 21 Stem Cell Signaling in the Heterogeneous Development of Medulloblastoma
21.1 Brain Tumor Cancer Stem Cells
21.3 Hijacking Cerebellar Development
21.3.1 Cerebellum Development
21.3.3 Sonic Hedgehog (SHH) Signaling
21.4 Molecular Classification of MB
21.4.2 Sonic Hedgehog (SHH) Subtype
21.5 Mouse Models and Cell of Origin
21.6 Additional Drivers of MB
21.6.1 Epigenetic Regulators
21.7 Repurposing Off-Patent Drugs
21.7.1 Repurposing Disulfiram (DSF)
21.8 Emerging Therapies for MB
Chapter 22 Induced Pluripotent Stem Cell-Derived Outer-Blood-Retinal Barrier for Disease Modeling and Drug Discovery
22.2 The Outer Blood-Retinal Barrier
22.3 iPSC-Based Model of the Outer-Blood-Retinal-Barrier
22.3.1 Stem Cell Technology Overview
22.3.2 Optimization of RPE Differentiation
22.3.3 Development of the Homeostatic Unit of the OBRB
22.4 iPSC Based OBRB Disease Models
22.4.1 Two-Dimensional iPSC-RPE Disease Models
22.4.1.1 Pigment Retinopathy
22.4.1.4 Age-Related Macular Degeneration
22.4.1.5 Bestrophin-Related Diseases
22.4.1.6 Leber Congenital Amurosis
22.4.1.7 Retinitis Pigmentosa
22.4.2 Development of Three-Dimensional Models
22.4.2.1 Autonomous Self-Assembly
22.4.2.2 Engineering Intervention
22.5 Applications of iPSC-Based Ocular Disease Models for Drug Discovery
22.5.1 High-Throughput Drug Screening
22.6 Conclusion and Future Directions
Chapter 23 Important Considerations in the Therapeutic Application of Stem Cells in Bone Healing and Regeneration
23.2 Stem Cells, Progenitor Cells, Mesenchymal Stem Cells
23.4 Animal Models in Bone Healing and Regeneration
23.4.1 Bone Regeneration Models
23.4.2 Clinical Trials in Bone Regeneration
23.5 Conclusions and Future Directions
Chapter 24 Stem Cells from Human Dental Tissue for Regenerative Medicine
24.2.1 Dental Pulp Stem Cells
24.2.2 Stem Cells from Human Exfoliated Deciduous Teeth
24.2.3 Periodontal Ligament Stem Cells
24.2.4 Dental Follicle Progenitor Cells
24.2.5 Alveolar Bone‐Derived Mesenchymal Stem Cells
24.2.6 Stem Cells from the Apical Papilla
24.2.7 Tooth Germ Progenitor Cells
24.2.8 Gingiva-Derived Mesenchymal Stem Cells
24.3 Potential Clinical Applications
24.3.2 Tooth Root Regeneration
24.3.3 Dentin‐Pulp Regeneration
24.3.4 Periodontal Regeneration
24.3.5 Neurological Disease
24.3.6 Lesions of the Cornea
24.3.7 Regeneration of Other Non‐Dental Tissues
24.3.8 Inflammatory and Allergic Diseases
24.5 Dental Stem Cell Banking
24.6 Conclusions and Perspective
Chapter 25 Stem Cells in the Skin
25.1.2 Skin Physiological Functions
25.1.3 Skin Regeneration and Skin Stem Cells
25.2 Stem Cells in the Skin
25.2.1 Epidermal Stem Cells
25.2.1.1 Hair Follicle Stem Cells (HFSCs)
25.2.1.2 The Interfollicular Epidermal Stem Cells
25.2.1.3 Sebaceous Stem Cells
25.2.1.4 Melanocyte stem cells
25.2.2 Stem Cells in the Dermals
25.2.3 Stem Cells in the Subcutaneous Tissue
25.3 Isolation and the Biological Markers of Skin Stem Cells
25.4 Skin Stem Cell Niches
25.5 Signaling Control of Stem Cell Differentiation
25.5.1 Wnt Signaling Pathway
25.5.2 MAPK Signaling Pathway
25.5.3 Notch Signaling Pathway
25.6 Stem Cells in Skin Aging
25.7 Stem Cells in Skin Cancer
25.8 Medical Applications of Skin Stem Cells
25.8.1 Stem Cells in Tissue Engineering and Skin Repair
25.8.2 Stem Cells in Hair Follicle Regeneration
25.8.3 Stem Cells in Wound Healing
25.9 Conclusions and Future Directions
Stem Cells in Toxicology and Medicine
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