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
Dr. Saura C. Sahu Research Chemist, Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, US Food and Drug Administration. Dr. Sahu is the US Editor for the Journal of Applied Toxicology and the editor of 'Hepatotoxicity' (Wiley, 2007), 'Toxicogenomics' (Wiley, 2008), 'Nanotoxicity' (Wiley, 2009), and 'Handbook of Systems Toxicology' (Wiley, 2011).
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
Dr. Saura C. Sahu Research Chemist, Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, US Food and Drug Administration. Dr. Sahu is the US Editor for the Journal of Applied Toxicology and the editor of "Hepatotoxicity" (Wiley, 2007), "Toxicogenomics" (Wiley, 2008), "Nanotoxicity" (Wiley, 2009), and "Handbook of Systems Toxicology" (Wiley, 2011).
Title Page 5
Copyright Page 6
Contents 9
List of Contributors 22
Preface 28
Acknowledgements 29
Part I 31
Chapter 1 Introduction 33
References 34
Chapter 2 Application of Stem Cells and iPS Cells in Toxicology 35
2.1 Introduction 35
2.2 Significance 36
2.3 Stem Cell (SC) Classification 37
2.4 Stem Cells and Pharmacotoxicological Screenings 38
2.5 Industrial Utilization Showcases Stem Cell Technology as a Research Tool 38
2.6 Multipotent Stem Cells (Adult Stem Cells) Characteristics and Current Uses 39
2.7 Mesenchymal Stem Cells (Adult Stem Cells) 40
2.8 Hematopoietic Stem Cells (Adult Stem Cells) 41
2.9 Cardiotoxicity 42
2.10 Hepatotoxicity 45
2.11 Epigenetic Profile 47
2.12 Use of SC and iPSC in Drug Safety 48
2.12.1 Potential Benefits of Stem Cell Use in Other Areas 48
2.12.2 Methodologies 48
2.12.3 Economic Benefits of Stem Cell Use 49
2.13 Conclusions and Future Applications 49
Acknowledgments 49
References 49
Chapter 3 Stem Cells: A Potential Source for High Throughput Screening in Toxicology 56
3.1 Introduction 56
3.2 Stem Cells 57
3.2.1 Embryonic Stem Cells (ESCs) 57
3.2.2 Foetal Stem Cells 59
3.2.3 Adult Stem Cells 59
3.2.4 Adult Stem Cells in Other Tissues 60
3.3 High Throughput Screening (HTS) 61
3.3.1 Current Strategies and Types of High Throughput Screening 62
3.3.2 In Vitro Biochemical Assays 63
3.3.2.1 Fluorescent Based Assays 63
3.3.2.2 Luminescence?Based Assays 63
3.3.2.3 Colorimetric and Chromogenic Assays 64
3.3.2.4 Mass Spectroscopy (MS) Based Detection Assays 64
3.3.2.5 Chromatography-Based Assays 64
3.3.2.6 Immobilization and Label-Free Detection Assays 65
3.3.3 Cell-Based Assays 65
3.3.3.1 Reporter Gene Assays 66
3.3.3.2 Cell-Based Label Free Readouts 66
3.4 Need for a Stem Cell Approach in High Throughput Toxicity Studies 67
3.5 Role of Stem Cells in High Throughput Screening for Toxicity Prediction 68
3.5.1 Applications of Stem Cells in Cardiotoxicity HTS 68
3.5.2 Applications of Stem Cells in Hepatotoxicity HTS 69
3.5.3 Applications of Stem Cells in Neurotoxicity HTS 70
3.6 Conclusion 70
Acknowledgement 71
Disclosure Statement 71
Author’s Contribution 71
References 71
Chapter 4 Human Pluripotent Stem Cells for Toxicological Screening 80
4.1 Introduction 80
4.2 The Biological Characteristics of hPSCs 81
4.2.1 The Biological Characteristics of hESCs 81
4.2.2 The Biological Characteristics of hiPSCs 81
4.3 Screening of Embryotoxic Effects using hPSCs 82
4.3.1 Screening of Embryotoxic Effects using hESCs 82
4.3.2 Screening of Embryotoxic Effects using hiPSCs 84
4.4 The Potential of hPSC-Derived Neural Lineages in Neurotoxicology 85
4.4.1 The Challenge of?hPSC?s-Derived Neural Lineages in Neurotoxicology Applications 85
4.4.2 The New Biomarkers in Neurotoxicology using?hPSC?-Derived Neural Lineages 86
4.4.2.1 Gene Expression Regulation 86
4.4.2.2 Epigenetic Markers 87
4.4.2.3 Mitochondrial Function 88
4.4.3 The New Methods in Neurotoxicology using?hPSC?-Derived Neural Lineages 88
4.4.3.1 High-Throughput Methods 88
4.4.3.2 Three-Dimensional (3-D) Culture 89
4.5 The Potential of?hPSC-Derived Cardiomyocytes in Cardiotoxicity 90
4.5.1 The Challenge of?hPSC-Derived Cardiomyocytes in Cardiotoxicology Applications 90
4.5.2 The New Biomarkers in Cardiotoxicology using?hPSC-Derived Cardiomyocytes 90
4.5.2.1 Gene Expression 91
4.5.2.2 Multi-Electrode Array 91
4.5.3 High-Throughput Methods 92
4.6 The Potential of hPSC-Derived Hepatocytes in Hepatotoxicity 92
4.6.1 The Challenge of hPSCs-Derived Hepatocytes in Hepatotoxicology Application 92
4.6.2 The New Biomarkers in Hepatotoxicology using hPSC?-Derived Hepatocytes 93
4.6.3 The New Methods in Hepatotoxicology using hPSC??Derived Hepatocytes 94
4.6.3.1 iPSC-HH-Based Micropatterned Co-Cultures (iMPCC?s) with Murine Embryonic Fibroblasts 94
4.6.3.2 Suspension Culture of Aggregates of ES Cell-Derived Hepatocytes 95
4.6.3.3 Long-Term Exposure to Toxic Drugs 95
4.7 Future Challenges and Perspectives for Embryotoxicity and Developmental Toxicity Studies using hPSCs 95
Acknowledgments 96
References 97
Chapter 5 Effects of Culture Conditions on Maturation of Stem Cell?Derived Cardiomyocytes 101
5.1 Introduction 101
5.2 Lengthening Culture Time 105
5.3 Substrate Stiffness 106
5.4 Structured Substrates 108
5.5 Conclusions 112
Disclaimer 112
References 113
Chapter 6 Human Stem Cell-Derived Cardiomyocyte In Vitro Models for Cardiotoxicity Screening 115
6.1 Introduction 115
6.1.1 Cardiotoxicity in Preclinical and Clinical Drug Development 115
6.1.2 Functional Cardiotoxicity 116
6.1.3 Structural Cardiotoxicity 117
6.1.4 Requirement for Improved In Vitro Models to Predict Human Cardiotoxicity 118
6.2 Overview of hPSC?Derived Cardiomyocytes 118
6.3 Human PSC-CM Models for Cardiotoxicity Investigations 120
6.3.1 hPSC-CMs for the Assessment of Electrophysiological Cardiotoxicity 120
6.3.1.1 Patch Clamp Assays 121
6.3.1.2 Voltage Sensitive Dyes (VSDs) 122
6.3.1.3 Optogenetics 123
6.3.1.4 Multielectrode Array (MEA) Assays 124
6.3.1.5 Impedance Assays 126
6.3.1.6 Calcium Imaging Assays 128
6.3.2 hPSC-CMs for the Assessment of Contractile Cardiotoxicity 128
6.3.2.1 Muscular Thin Films 129
6.3.2.2 Engineered Heart Tissues (EHTs) 129
6.3.2.3 Impedance Assays 131
6.3.2.4 Calcium Imaging Assays 132
6.3.3 hPSC-CMs for the Assessment of Structural Cardiotoxicity 132
6.3.3.1 Mechanisms of Cardiomyocyte Cell Death as Endpoints in Drug Screening 133
6.3.3.2 High Content Analysis 136
6.3.3.3 Impedance Assays 138
6.3.3.4 SeaHorse Flux Analysers 139
6.3.3.5 Complex and 3D Models 140
6.4 Conclusions and Future Direction 142
References 142
Chapter 7 Disease-Specific Stem Cell Models for Toxicological Screenings and Drug Development 152
7.1 Evidence for Stem Cell?Based Drug Development and Toxicological Screenings in Psychiatric Diseases, Cardiovascular Diseases and Diabetes 152
7.1.1 Introduction into Stem-Cell Based Drug Development and Toxicological Screenings 152
7.1.2 Relevance for Psychiatric and Cardiovascular Diseases 153
7.1.3 Advantages of Human Disease-Specific Stem Cell Models 154
7.1.4 Pluripotent Stem Cell Models 155
7.1.5 Reprogramming of Somatic Cells for Disease-Specific Stem Cell Models 156
7.1.6 Transdifferentation of Somatic Cells for Disease-Specific Stem Cell Models 156
7.2 Disease-Specific Stem Cell Models for Drug Development in Psychiatric Disorders 157
7.2.1 Disease-Specific Stem Cell Models Mimicking Neurodegenerative Disorder 157
7.2.2 Disease-Specific Stem Cell Models Mimicking AD 158
7.2.3 Disease-Specific Stem Cell Models Mimicking Neurodevelopmental Disorders 159
7.2.4 Disease-Specific Stem Cell Models Mimicking SCZ 161
7.3 Stem Cell Models for Cardiotoxicity and Cardiovascular Disorders 162
7.3.1 Generating Cardiomyocytes In Vitro 162
7.3.2 Generating Microphysiological Systems to Mimic the Human Heart 163
7.3.3 Disease-Modeling using Microphysiological Cardiac Systems 163
7.4 Stem Cell Models for Toxicological Screenings of EDCs 163
7.4.1 In Vitro Analysis of EDCs in Reproduction and Development 164
7.4.2 In Vitro Analysis and Toxicological Screenings of Drugs 165
References 165
Chapter 8 Three-Dimensional Culture Systems and Humanized Liver Models Using Hepatic Stem Cells for Enhanced Toxicity Assessment 175
8.1 Introduction 175
8.2 Hepatic Cell Lines and Primary Human Hepatocytes 176
8.3 Embryonic Stem Cells and Induced Pluripotent Stem?Cell Derived Hepatocytes 177
8.4 Ex Vivo: Three-Dimensional and Multiple-Cell Culture System 178
8.5 In Vivo: Humanized Liver Models 179
8.6 Summary 180
Acknowledgments 180
References 180
Chapter 9 Utilization of In Vitro Neurotoxicity Models in Pre?Clinical Toxicity Assessment 185
9.1 Introduction 185
9.1.1 Limitations of Animal Models and the Utility of In Vitro Assays for Neurotoxicity Testing 185
9.1.2 How Regulatory Requirements Can Shape the Development of In Vitro Screening Tools and Efforts 187
9.1.3 In Vitro Assays as Useful Tools for Assessing Neurotoxicity in a Pharmaceutical Industry Setting 188
9.2 Current Models of Drug?Related Clinical Neuropathies and Effects on Electrophysiological Function 189
9.2.1 Neuropathy Assessment 190
9.2.2 Seizure Potential and Electrophysiological Function Assessments 191
9.2.3 Multi Electrode Arrays to Model Electrophysiological Changes Upon Drug Treatment 191
9.3 Cell Types that Can Potentially Be Used for In Vitro Neurotoxicity Assessment in Drug Development 192
9.3.1 Primary Cells Harvested from Neuronal Tissues 192
9.3.2 Immortalized Cells and Cell Lines 194
9.3.3 Induced Pluripotent Stem (iPS) Derived Cells 195
9.4 Utility of iPSC Derived Neurons in In Vitro Safety Assessment 197
9.4.1 iPSC Derived Neurons in Electrophysiology 197
9.4.2 iPSC Derived Neurons to Study Neurite Dynamics 197
9.5 Summary of Key Points for Consideration in Neurotoxicity Assay Development 200
9.6 Concluding Remarks 202
References 202
Chapter 10 A Human Stem Cell Model for Creating Placental Syncytiotrophoblast, the Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics 209
10.1 Introduction 209
10.2 General Features of Placental Structure 210
10.3 The Human Placenta 210
10.4 Human Placental Cells in Toxicology Research 212
10.5 Placental Trophoblast Derived from hESC 213
10.6 Isolation of Syncytial Areas from BAP?Treated H1 ESC Colonies 215
10.7 Developmental Regulation of Genes Encoding Proteins Potentially Involved in Metabolism of Xenobiotics 215
10.7.1 Cytochrome P450 Family Members 216
10.7.2 SLC Gene Family Members 218
10.7.3 ATP-Binding Cassette (ABC) Transporters 219
10.7.4 Metallothionein Family Members 220
10.8 Concluding Remarks 221
Acknowledgments 222
References 222
Chapter 11 The Effects of Endocrine Disruptors on Mesenchymal Stem Cells 226
11.1 Mesenchymal Stem Cells 226
11.1.1 Characterization 226
11.1.2 Differentiation 227
11.1.2.1 Adipogenic 227
11.1.2.2 Osteogenic 227
11.1.3 Functions and Activities 227
11.2 Endocrine Disruptors 228
11.2.1 EDC Major Epidemiologic Associations 228
11.2.1.1 EDC Association with Obesity 228
11.2.1.2 EDC Association with Diabetes 229
11.2.2 Challenges with Exposure Study Interpretation in Human Subjects 229
11.2.2.1 Nonmonotonicity of EDC Dose?Response Curves 229
11.2.2.2 EDC Exposure at Critical Developmental Windows and Association with Adult Disease 230
11.2.2.3 Effects of Combinations of EDCs 230
11.2.3 Mechanisms of Action of EDCs 231
11.3 Pesticides 231
11.3.1 Organophosphates 231
11.3.1.1 Cell-Type Specific Effects 231
11.3.1.2 Molecular Effects 233
11.3.2 DDT 235
11.3.2.1 Cell-Specific Effects 235
11.3.2.2 Molecular Effects 236
11.4 Alkyl Phenols and Derivatives 236
11.4.1 Cell-Specific Effects 238
11.4.1.1 Effects on Adipocytes and Precursors of Adipocytes 238
11.4.1.2 Effects on Osteoblasts and Precursors of Osteoblasts 239
11.4.2 Molecular Effects 239
11.5 Bisphenol A 241
11.5.1 Cell-Specific Effects 241
11.5.1.1 Effects on Adipocytes and Precursors of Adipocytes 242
11.5.1.2 Effects on Osteoblasts and Precursors of Osteoblasts 244
11.5.2 Molecular Effects 244
11.6 Polychlorinated Biphenyls 246
11.6.1 Cell-Specific Effects 247
11.6.1.1 Effects on Adipocytes and Precursors of Adipocytes 247
11.6.1.2 Effects on Osteoblasts and Precursors of Osteoblasts 248
11.6.2 Molecular Effects 250
11.7 Phthalates 251
11.7.1 Cell-Specific Effects 252
11.7.1.1 Effects on Adipocytes and Precursors of Adipocytes 252
11.7.1.2 Effects on Osteoblasts and Precursors of Osteoblasts 253
11.7.2 Molecular Effects 255
11.8 Areas for Future Research 255
11.9 Conclusions 256
Abbreviations 256
References 258
Chapter 12 Epigenetic Landscape in Embryonic Stem Cells 268
12.1 Introduction 268
12.2 DNA Methylation in ESCs 269
12.3 Histone Methylation in ESCs 270
12.4 Chromatin Remodeling and ESCs Regulation 271
12.5 Concluding Remarks 272
Acknowledgements 273
References 273
Part II 277
Chapter 13 The Effect of Human Pluripotent Stem Cell Platforms on Preclinical Drug Development 279
13.1 Introduction 279
13.2 Core Signaling Pathways Underlying hPSC Stemness and Differentiation 280
13.3 Basic Components of In Vitro and Ex Vivo hPSC Platforms 281
13.3.1 Growth Medium Development for Drug Discovery 281
13.3.2 Choices of Extracellular Components 282
13.4 Diverse hPSC Culture Platforms for Drug Discovery 282
13.4.1 Colony Type Culture-Based Modules 283
13.4.2 Suspension Culture 283
13.4.3 Non-Colony Type Monolayer Empowers Efficient Drug Screening 283
13.4.4 Tissue Integration: Morphogenesis and Organogenesis 284
13.5 Representative Analyses of hPSC?Based Drug Discovery 285
13.5.1 Neuroectodermal Disease Models for Drug Assessment 285
13.5.2 Hepatic Models for Drug Assessment 286
13.5.3 Cardiomyocytes for Cancer Drug Discovery 286
13.6 Current Challenges and Future Considerations 287
13.6.1 Dimensionality, Maturity, and Functionality of Differentiated Cells 288
13.6.2 Complexity: Genetics versus Epigenetics 289
13.6.3 Other Notable Factors 289
13.7 Concluding Remarks 290
Acknowledgments 290
References 290
Chapter 14 Generation and Application of 3D Culture Systems in Human Drug Discovery and Medicine 295
14.1 Introduction 295
14.2 Traditional Scaffold-Based Tissue Engineering 296
14.2.1 Materials for Fabrication of Scaffolds 296
14.2.1.1 Naturally Occurring Polymers 296
14.2.1.2 Biodegradable Synthetic Polymers 297
14.2.1.3 Bioactive Glass and Glass Ceramics 297
14.2.1.4 Hydrogels 297
14.2.2 Fabrication Methods 298
14.2.2.1 Photolithography 298
14.2.2.2 Soft Lithography 298
14.2.2.3 Microfluidics 298
14.2.2.4 Emulsification 299
14.3 Scaffold-Free 3D Culture Systems 299
14.4 Modular Biofabrication 300
14.5 3D Bioprinting 300
14.5.1 Bioprinting Strategies 301
14.5.1.1 Microextrusion Bioprinting Technology 301
14.5.1.2 Inkjet Bioprinting Technology 301
14.5.1.3 Laser-Assisted Bioprinting Technology 302
14.6 Tissue Modelling and Regenerative Medicine Applications of Pluripotent Stem Cells 302
14.6.1 The In Vitro Hepatic Models 303
14.7 Applications in Drug Discovery and Toxicity 305
14.7.1 3D Culture Systems 306
14.7.2 Liver In Vitro Models for Drug Discovery, Toxicity, and Modelling Drug Metabolism 307
14.7.3 Microfluidics 308
14.8 Conclusions 308
References 308
Chapter 15 Characterization and Therapeutic Uses of Adult Mesenchymal Stem Cells 318
15.1 Introduction 318
15.2 MSC Characterization 319
15.2.1 MSC Negative Markers 319
15.2.2 MSC Positive Markers 319
15.2.3 MSC Self-Renewal and Maintenance 320
15.2.4 MSCs Proliferate in Hypoxia Faster than in Normoxia 320
15.2.5 MSCs Kill Bacteria by Autophagy 320
15.2.6 MSCs Exhibit Mitochondrial Remodeling 322
15.2.7 MSCs and Signal Transduction 322
15.3 MSCs and Tissue or Organ Therapy 323
15.3.1 MSCs Improve Acute Lung Injury 323
15.3.2 MSCs Improve Renovascular Function in the Kidney 324
15.3.3 MSCs Effectively Treat Articular Cartilage Defects and Osteoarthritis 324
15.3.4 Differentiated MSCs Improve Myocardial Performance 324
15.3.5 MSCs Improve Radiation-Induced Damage in the Intestinal Mucosal Barrier 325
15.3.6 MSCs Repair Radiation-Induced Liver Injury 325
15.3.7 MSCs Accelerate Radiation-Induced Delay in Wound Healing 325
15.3.8 MSCs Improve Radiation-Induced Cognitive Dysfunction 326
15.3.9 MSCs Improve Survival after Ionizing Radiation Combined Injury 326
15.3.10 MSCs Attenuate the Severity of Acute Graft-Versus-Host Disease 327
15.3.11 MSCs Preconditioned with Mood Stabilizers Enhances Therapeutic Efficacy for Stroke and Huntington’s Disease 328
15.4 Conclusions 328
Acknowledgments 328
References 328
Chapter 16 Stem Cell Therapeuticsfor Cardiovascular Diseases 333
16.1 Introduction 333
16.2 Types of Stem/Progenitor Cell-Derived Endothelial Cells 334
16.2.1 ESCs/iPSCs 334
16.2.2 MSCs 335
16.2.3 MNCs 335
16.2.4 EPCs 335
16.3 EPC and Other Stem/Progenitor Cell Therapy in CVDs 336
16.3.1 EPC Therapy for Ischemic Vascular Diseases (PAD/HLI) 336
16.3.2 EPC Therapy for Ischemic Cardiac Diseases (MI) 336
16.3.3 EPC Therapy in Clinical Trials for CVDs 336
16.4 Strategies and Approaches for Enhancing EPC Therapy in CVDs 336
16.5 Concluding Remarks 345
Acknowledgments 346
References 346
Chapter 17 Stem-Cell-Based Therapies for Vascular Regeneration in Peripheral Artery Diseases 354
17.1 Sources of Stem Cells for Vascular Regeneration 355
17.1.1 Adult Stem Cells 355
17.1.2 Umbilical Cord-Blood-Derived Stem Cells 357
17.1.3 Embryonic Stem Cells 357
17.1.4 Induced Pluripotent Stem Cells 358
17.2 Canonic Mechanisms Governing Vascular Stem Cells Therapeutic Potential 359
17.2.1 Differentiation into Vascular Cells 359
17.2.2 The Paracrine Effect 360
17.2.2.1 Pro-Angiogenic Factor 360
17.2.2.2 Vasoactive Factors 361
17.2.2.3 Extracellular Membrane Vesicles 361
17.2.3 Interaction with the Host Tissue 362
17.3 Stem-Cell-Based Therapies in Patients with Peripheral Artery Disease 363
17.3.1 Mononuclear Cells from Bone Marrow and Peripheral Blood 365
17.3.2 Selected Cell Population 366
17.3.3 Endothelial Progenitor Cells 366
References 367
Chapter 18 Gene Modified Stem/Progenitor-Cell Therapy for Ischemic Stroke 377
18.1 Introduction 377
18.2 Gene Modified Stem Cells for Ischemic Stroke 378
18.2.1 Gene Modified Mesenchymal Stem Cells 379
18.2.2 Gene Modified Neural Stem Cells 382
18.2.3 Gene Modified Endothelial Progenitor Cells 383
18.2.4 Induced Pluripotent Stem Cells 384
18.3 Gene Transfer Vectors 384
18.3.1 Viral Vectors 384
18.3.2 Non-Viral Vectors 385
18.4 Unsolved Issues for Gene?Modified Stem Cells in Ischemic Stroke 386
18.5 Conclusion 386
Abbreviations 386
Acknowledgments 387
References 387
Chapter 19 Role of Stem Cells in the Gastrointestinal Tract and in the Development of Cancer 393
19.1 Introduction 393
19.2 GI Development and Regeneration 395
19.2.1 GI Development 395
19.2.2 GI Stem Cells and Liver Regeneration 395
19.3 GI Tumorigenesis and Stemness Gene Expression 397
19.4 Toxicants and Other Stress Trigger Epigenetic Changes, Dedifferentiation, and Carcinogenesis 398
19.5 Summary and Perspective 399
Acknowledgments 399
References 400
Chapter 20 Cancer Stem Cells: Concept, Significance, and Management 405
20.1 Introduction 405
20.2 Stem Cells and Cancer: Historical Perspective 406
20.3 Cancer Stem Cells 407
20.3.1 The Origin of Cancer Stem Cells 408
20.3.1.1 Genetic Instability and Cell Fusion 408
20.3.1.2 Horizontal Gene Transfer 411
20.3.1.3 Microenvironment 411
20.4 Identification and Isolation of CSCs 412
20.4.1 CD133 413
20.4.2 CD24 414
20.4.3 CD44 414
20.4.4 EpCAM 415
20.4.5 CD177 415
20.4.6 CD34 416
20.4.7 ALDH1 416
20.4.8 CXCR4 416
20.4.9 Side Population 417
20.5 Pathological Significance of Cancer Stem Cells 418
20.6 Pathways Regulating Cancer Stem Cells 419
20.6.1 Oct4 420
20.6.2 Sox2 420
20.6.3 Nanog 421
20.6.4 KLF4 421
20.6.5 Notch 422
20.6.6 Wnt 422
20.6.7 Hedgehog 423
20.6.8 Micro RNAs 423
20.7 Therapeutic Strategies Targeting Cancer Stem Cells 424
20.7.1 Targeting CSC-Specific Markers 424
20.7.2 Targeting CSC-Specific Molecular Signaling Pathways 426
20.7.3 CSC-Related Immunotherapy 427
20.7.4 Targeting CSC Microenvironment 428
20.8 Conclusion and Future Directions 429
References 430
Chapter 21 Stem Cell Signaling in the Heterogeneous Development of Medulloblastoma 444
21.1 Brain Tumor Cancer Stem Cells 444
21.2 Medulloblastoma 446
21.3 Hijacking Cerebellar Development 447
21.3.1 Cerebellum Development 447
21.3.2 WNT?Signaling 447
21.3.3 Sonic Hedgehog (SHH) Signaling 448
21.3.4 BMP Signaling 450
21.3.5 NOTCH Signaling 450
21.4 Molecular Classification of MB 450
21.4.1 WNT Subtype 451
21.4.2 Sonic Hedgehog (SHH) Subtype 452
21.4.3 Group 3 Subtype 452
21.4.4 Group 4 Subtype 453
21.5 Mouse Models and Cell of Origin 454
21.6 Additional Drivers of MB 455
21.6.1 Epigenetic Regulators 456
21.6.2 TP53 456
21.7 Repurposing Off-Patent Drugs 456
21.7.1 Repurposing Disulfiram (DSF) 457
21.8 Emerging Therapies for MB 458
21.9 Conclusion 459
Acknowledgments 459
References 459
Chapter 22 Induced Pluripotent Stem Cell-Derived Outer-Blood-Retinal Barrier for Disease Modeling and Drug Discovery 466
22.1 Introduction 466
22.2 The Outer Blood-Retinal Barrier 467
22.3 iPSC-Based Model of the Outer-Blood-Retinal-Barrier 469
22.3.1 Stem Cell Technology Overview 469
22.3.2 Optimization of RPE Differentiation 470
22.3.3 Development of the Homeostatic Unit of the OBRB 471
22.4 iPSC Based OBRB Disease Models 472
22.4.1 Two-Dimensional iPSC-RPE Disease Models 473
22.4.1.1 Pigment Retinopathy 474
22.4.1.2 Gyrate Atrophy 474
22.4.1.3 Choroideremia 474
22.4.1.4 Age-Related Macular Degeneration 475
22.4.1.5 Bestrophin-Related Diseases 475
22.4.1.6 Leber Congenital Amurosis 475
22.4.1.7 Retinitis Pigmentosa 476
22.4.2 Development of Three-Dimensional Models 476
22.4.2.1 Autonomous Self-Assembly 477
22.4.2.2 Engineering Intervention 477
22.5 Applications of iPSC-Based Ocular Disease Models for Drug Discovery 478
22.5.1 High-Throughput Drug Screening 478
22.5.2 Microfluidics 479
22.6 Conclusion and Future Directions 481
References 481
Chapter 23 Important Considerations in the Therapeutic Application of Stem Cells in Bone Healing and Regeneration 488
23.1 Introduction 488
23.2 Stem Cells, Progenitor Cells, Mesenchymal Stem Cells 489
23.3 Scaffolds 491
23.3.1 Graphene 492
23.4 Animal Models in Bone Healing and Regeneration 494
23.4.1 Bone Regeneration Models 494
23.4.2 Clinical Trials in Bone Regeneration 496
23.5 Conclusions and Future Directions 502
References 502
Chapter 24 Stem Cells from Human Dental Tissue for Regenerative Medicine 511
24.1 Introduction 511
24.2 Dental Stem Cells 512
24.2.1 Dental Pulp Stem Cells 512
24.2.2 Stem Cells from Human Exfoliated Deciduous Teeth 514
24.2.3 Periodontal Ligament Stem Cells 514
24.2.4 Dental Follicle Progenitor Cells 515
24.2.5 Alveolar Bone?Derived Mesenchymal Stem Cells 516
24.2.6 Stem Cells from the Apical Papilla 516
24.2.7 Tooth Germ Progenitor Cells 517
24.2.8 Gingiva-Derived Mesenchymal Stem Cells 517
24.3 Potential Clinical Applications 518
24.3.1 Bone Regeneration 518
24.3.2 Tooth Root Regeneration 518
24.3.3 Dentin?Pulp Regeneration 519
24.3.4 Periodontal Regeneration 519
24.3.5 Neurological Disease 520
24.3.6 Lesions of the Cornea 520
24.3.7 Regeneration of Other Non?Dental Tissues 521
24.3.8 Inflammatory and Allergic Diseases 521
24.4 Safety 522
24.4.1 Immune Rejection 522
24.4.2 Tumor Formation 523
24.5 Dental Stem Cell Banking 523
24.6 Conclusions and Perspective 524
Chapter 25 Stem Cells in the Skin 532
25.1 Introduction 532
25.1.1 Skin Structure 532
25.1.2 Skin Physiological Functions 532
25.1.3 Skin Regeneration and Skin Stem Cells 533
25.2 Stem Cells in the Skin 533
25.2.1 Epidermal Stem Cells 534
25.2.1.1 Hair Follicle Stem Cells (HFSCs) 534
25.2.1.2 The Interfollicular Epidermal Stem Cells 534
25.2.1.3 Sebaceous Stem Cells 534
25.2.1.4 Melanocyte stem cells 535
25.2.2 Stem Cells in the Dermals 535
25.2.3 Stem Cells in the Subcutaneous Tissue 536
25.3 Isolation and the Biological Markers of Skin Stem Cells 536
25.4 Skin Stem Cell Niches 538
25.5 Signaling Control of Stem Cell Differentiation 540
25.5.1 Wnt Signaling Pathway 540
25.5.2 MAPK Signaling Pathway 541
25.5.3 Notch Signaling Pathway 543
25.6 Stem Cells in Skin Aging 544
25.7 Stem Cells in Skin Cancer 546
25.8 Medical Applications of Skin Stem Cells 548
25.8.1 Stem Cells in Tissue Engineering and Skin Repair 548
25.8.2 Stem Cells in Hair Follicle Regeneration 549
25.8.3 Stem Cells in Wound Healing 549
25.9 Conclusions and Future Directions 550
References 551
Author Index 557
Subject Index 559
Supplemental Images 563
EULA 591
| Erscheint lt. Verlag | 13.10.2016 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Physiotherapie / Ergotherapie ► Orthopädie |
| Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik | |
| Studium ► 2. Studienabschnitt (Klinik) ► Pharmakologie / Toxikologie | |
| Naturwissenschaften ► Chemie ► Technische Chemie | |
| Technik | |
| Schlagworte | Alzheimer's • Biowissenschaften • Cell & Molecular Biology • Cell Biology • Chemie • Chemistry • Life Sciences • Medical Science • Medizin • neurodegenerative diseases • Parkinson's Disease • Stammzelle • Stem Cells • Toxicology • Toxikologie • Zellbiologie • Zell- u. Molekularbiologie |
| ISBN-10 | 1-119-13542-7 / 1119135427 |
| ISBN-13 | 978-1-119-13542-5 / 9781119135425 |
| Informationen gemäß Produktsicherheitsverordnung (GPSR) | |
| Haben Sie eine Frage zum Produkt? |
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