Stem Cell Biology in Health and Disease (eBook)

Preface 5
Contents 7
Contributors 9
1 Introduction 13
References 18
Part I Bone Marrow-Derived Stem Cells 20
2 Hematopoietic Stem and Progenitor Cells in Clinical Use Transplantation and Mobilization 21
2.1 Historical Aspects 22
2.2 Stem Cell Donors 23
2.3 Stem Cell Mobilization and Autologous Transplantation 25
2.4 Allogeneic Transplantation 27
2.5 Outlook 30
References 31
3 Ex Vivo Expansion of HSPCs 37
3.1 The Sources of HSPCs 38
3.1.1 Bone Marrow HSPCs 38
3.1.2 Peripheral HSPCs 39
3.1.3 Umbilical Cord Blood HSPCs 39
3.2 The Expansion of HSPCs 40
3.2.1 Cytokines 41
3.2.2 Ex Vivo Expansion of HSPCs 41
3.2.3 Regulation of HSPCs Expansion 44
3.2.4 Free Radical Regulation on HSPCs Expansion 45
3.2.5 Megakaryocytic Progenitor Cells Expansion 46
3.2.6 Red Cells Expansion 46
3.2.7 T-Cell Expansion 47
3.2.8 NK Cell Expansion 48
3.2.9 DC Expansion 49
3.2.10 HSPC Ex Vivo Expansion and Gene Therapy 51
3.3 Expansion Bioreactor 51
3.4 The Application of Expanded HSPCs 54
3.4.1 Transplantation of HSPCs in Animal Model 54
3.4.2 Transplantation of HSPCs in Human 57
3.5 The Future of HSPCs Expansion 58
References 58
4 Modulation of Hematopoietic Stem/Progenitor Cell Migration 67
4.1 Introduction 68
4.2 The SDF-1/CXCR4 Axis 68
4.2.1 Stromal Cell-Derived Factor-1 (SDF-1) 68
4.2.2 CXCR4 69
4.2.3 SDF-1/CXCR4 Signaling 70
4.3 Homing of HSPCs to Bone Marrow and Organs 71
4.4 Influence of Culture Conditions on the Migration of Human CD34+/CD133+ Cord Blood HSPCs 73
4.5 Influence of Culture Conditions on the Migration of Murine Lin- c-kit+ HSPCs 76
4.6 Termination of the SDF-1 Induced Migration of HSPCs 78
4.7 Conclusion 82
References 83
5 Properties of Mesenchymal Stem Cells to Consider for Cancer Cell Therapy 88
5.1 Identifying MSCs 89
5.2 Tissue Origin of MSCs 90
5.3 Induced Pluripotent Stem Cells and MSCs 91
5.4 MSC Homing in Tissue Repair and Oncogenesis 91
5.5 MSCs Tumor Tropism and Pro-metastatic Effects 92
5.6 Chemokine Receptors Regulating MSCs Homing 94
5.7 Growth Factor Receptors Regulating MSCs Homing 95
5.8 Toll-Like Receptors and Death Receptors in MSC Migration 95
5.9 Oncogenic Potential of MSCs 96
5.10 Immunosuppressive Effects of MSCs 97
5.10.1 T Cells 97
5.10.2 NK Cells 97
5.10.3 DCs 98
5.10.4 B Cells 98
5.11 Modulation of MSCs Immunosuppression 98
5.12 MSCs for Cellular Gene Therapy 99
5.13 Retroviral Vectors for MSC Gene Transfer 99
5.14 Electroporation for MSC Gene Transfer 100
5.15 Ex Vivo Reprogramming of MSCs Without Gene Transfer 100
5.16 Cytokine-Producing MSCs for Cancer Cell Therapy 100
5.17 Oncolytic Virus-Infected MSCs 101
5.18 Conclusion 102
References 102
Part II Embryonic Stem Cells 108
6 Alternative Embryonic Stem Cell Sources 109
6.1 Introduction 110
6.2 Embryonal Carcinoma (EC) Cells 110
6.3 Embryonic Stem (ES) Cells 111
6.3.1 Hallmarks of ES Cells 112
6.3.2 Regulation of Self-Renewal and Pluripotency of ES Cells 112
6.3.2.1 Extrinsic Factors 113
6.3.2.2 Transcriptional Regulation 116
6.3.2.3 Epigenetic Regulation 118
6.3.2.4 MicroRNAs 119
6.4 Alternative Sources of Pluripotent Stem Cells 121
6.4.1 Derivation of Pluripotent Stem Cells by Reprogramming of a Somatic Nucleus 122
6.4.1.1 Somatic Cell Nuclear Transfer (SCNT) 122
6.4.1.2 Cytoplasmic Hybrids 123
6.4.1.3 Altered Nuclear Transfer (ANT) 123
6.4.1.4 Nuclear Reprogramming by Cell Fusion 124
6.4.1.5 Nuclear Reprogramming by Cell Extracts 125
6.4.1.6 Nuclear Reprogramming by Defined Transcription Factors 127
6.4.1.7 Alternative Ways for Obtaining Pluripotent Stem Cells from Early Embryos 137
6.4.2 Pluripotent Stem Cells Derived from Germ Cells 138
6.4.2.1 Pluripotent Stem Cells from Testis 138
6.4.2.2 Pluripotent Stem Cells from Oocytes 138
6.5 Future Prospects and Conclusions 140
References 142
7 Cell Therapy in Parkinsons Disease 152
7.1 Introduction 152
7.2 Fetal Ventral Mesencephalon 154
7.3 Fetal Neural Precursor Cells 155
7.4 Embryonic Stem Cells 156
7.5 Induced Pluripotent Stem Cells (iPS Cells) 157
7.6 Adult Stem Cells 158
7.7 Conclusions 158
References 159
8 Transplantation of Stem Cells and Their Derivatives in the Treatment of Multiple Sclerosis 162
8.1 Introduction 163
8.2 The Pathology of Multiple Sclerosis 164
8.3 Current Treatments for Multiple Sclerosis 166
8.4 The Need for Repair-Oriented Therapies for Multiple Sclerosis 167
8.4.1 Transplantation of Exogenous Stem Cells 167
8.4.2 Mobilization of Endogenous Stem Cells 168
8.5 Which Exogenous Stem Cells Can Be Used for Transplantation? 168
8.5.1 Embryonic Stem Cells 168
8.5.2 Induced Pluripotent Stem Cells 170
8.5.3 Neural Stem Cells 172
8.5.4 Hematopoietic Stem Cells (HSCs) and Mesenchymal Stem Cells (MSCs) 172
8.6 Stem Cells and Stem Cell-Derived Precursors are Capable of Myelination in Animal Models 174
8.6.1 Remyelination in Genetic Disease Models 174
8.6.2 Remyelination Following Chemically-Induced Demyelination 176
8.7 Studies of Stem Cells in Experimental Autoimmune Encephalomyelitis Models 176
8.7.1 Survival and Migration of Stem Cell-Derived Progenitors in EAE 177
8.7.2 Immunomodulatory Effects of Stem Cell-Derived Progenitors in EAE 178
8.7.3 Remyelination by Stem Cell-Derived Progenitors in EAE 178
8.8 Initial Investigations into Exogenous Cell-Based Therapy in Multiple Sclerosis 179
8.9 Future Directions 179
8.9.1 Establishing the Myelinating Capacity of Stem Cells in MS 179
8.9.2 Inflammation and Astrocytes 180
8.9.3 Method of Cell Delivery to MS Patients 180
8.9.4 The Use of Genetically Modified Cells for Transplantation 181
8.9.5 Selection of MS Patients for Transplantation Therapy 182
References 182
Part III Cancer Stem Cells 189
9 Cancer: A Stem Cell-based Disease? 190
9.1 Introduction 191
9.2 Evolution of Homeostatic Control of the Hierarchical and Cybernetic Nature of Human Health 192
9.3 The Concept of Stem Cells in the Evolutionary Transition from Single Cell Organisms and the Metazoan 195
9.4 Gap Junctional Intercellular Communication as the Evolutionary Biological Rosetta Stone for Understanding the Homeostatic Regulation of Cellular Functions in Metazoans 197
9.5 Cancer as the Result of a Disease of Homeostatic Control of Cell Communication 199
9.6 Role of Gap Junctions in the Multi-Stage/Multi-Mechanism Hypothesis of Carcinogenesis 200
9.7 What Is Source of the Initiated Cell? 205
9.8 Adult Stem Cells, Immortalizing Viruses and Cancers: 208
9.9 Tumors and Tumor Cell Lines: A Mixture of Cancer Stem Cells and Cancer Non-stem Cells 209
9.10 Characteristics of Normal Adult Stem Cells, Cancer Stem Cells and Cancer Non-stem Cells 211
9.11 Cancer Stem Cells, Drug-Resistant Cancer Cells and Side-Population Cells 212
9.12 Two Types of Cancer Cells 213
9.13 Stem Cells, Hypoxia, Drug Resistance and Oct-4 A 214
9.14 Dietary Modulation of Cancer: The Barker Hypothesis, Stem Cell Frequency and Risk to Cancer 215
9.15 Does the Adult Stem Cell or the Differentiated Somatic Cell Act as the Target Cell for the Initiation of Cancer 217
9.16 Conclusion 218
References 219
10 Stem Cell Niche Versus Cancer Stem Cell Niche Differences and Similarities 228
10.1 Introduction 229
10.2 The Stem Cell Niche in Normal Tissue 229
10.3 The Inflammatory Niche 232
10.4 The Immunological Niche 233
10.5 The Tumor Cell Niche 234
10.6 Conclusion 235
References 235
11 The Chronically Inflamed Microenvironment and Cancer Stem Cells 239
11.1 Introduction 239
11.2 The Association of Inflammation and Cancer 240
11.3 What Does the Chronic Inflammatory Environment Look Like? 242
11.4 What are the Long Term Effects of Chronic Inflammation? 246
11.5 Inflammation and Tumors Inflammations Many Roles 247
11.6 Summary 248
References 250
12 Does the Chronically Inflamed Periodontium Harbour Cancer Stem Cells? 255
12.1 Introduction 256
12.2 Stem Cells and Periodontal Tissue Regeneration 260
12.3 Animal Models in Periodontal Research 262
12.4 Tumor Induction Mediated by pdSCs? 263
12.5 Discussion 266
12.5.1 Stem Cells in the Periodontium 266
12.5.2 The Periodontal Defect 269
12.5.3 Source of pdSCs 273
12.5.4 Special Features 273
12.5.5 Considering the Nude Rats 273
12.5.6 pdSCs and Tumor Initiation 274
12.6 Conclusion 277
12.6.1 Periodontal Stem Cells as Functional Elements of Regenerative Periodontology 277
12.6.2 Possible Periodontal Tissue Regeneration 278
References 278
13 Leukemia Stem Cells 284
13.1 Introduction 285
13.2 Stem cells in acute myeloid leukemia are defined by their ability to reconstitute leukemia in serially transplanted NOD/SCID mice 285
13.3 Phenotype of Leukemia Stem Cells in AML 286
13.4 Leukemia Stem Cells in CML 287
13.5 Stem Cells in Acute Lymphoblastic Leukemia (ALL) 288
13.6 Identity of Leukemia Stem Cells in ALL Is Controversial 289
13.7 Leukemia Stem Cells and Drug-Resistance in ALL 289
13.8 Mechanisms of Leukemia Stem Cell Self-renewal 290
13.8.1 The PTEN/PI3K/AKT/FOXO Axis 290
13.8.2 Deregulation of CDX2/HOX Genes 291
13.8.3 Nuclear Reprogramming by OCT4 291
13.8.4 WNT/ -Catenin Signaling Pathway 292
13.9 Perspective 293
References 294
14 Cancer Stem Cells in Solid Tumors 298
14.1 Introduction 299
14.2 Finding the Needle in the Haystack: Identifying Phenotypically Distinct Prospective Cancer Stem Cells 300
14.2.1 Sphere Assays 300
14.2.2 Side Population Cells 303
14.2.3 Cancer Stem Cell Markers 305
14.2.3.1 Brain 306
14.2.3.2 Breast 308
14.2.3.3 Colon 311
14.2.3.4 Head and Neck 311
14.2.3.5 Kidney 311
14.2.3.6 Liver 312
14.2.3.7 Ovary 312
14.2.3.8 Pancreas 313
14.2.3.9 Prostate 314
14.2.3.10 Skin 315
14.3 Cell of Origin of Cancer Stem Cells 316
14.4 Perspectives and Challenges 322
References 324
15 One for All or All for One? The Necessity of Cancer Stem Cell Diversity in Metastasis Formation and Cancer Relapse 330
15.1 Introduction 331
15.2 The Necessity of Different CSC Subtypes 333
15.3 The Origin of Primary Tumor CSCs 334
15.3.1 Do pCSCs Originate from Adult Stem Cells? 334
15.3.2 Do pCSCs Originate from Progenitor Cells? 336
15.3.3 Do pCSCs Originate from Cell Fusion Events? 338
15.4 Metastatic CSCs 339
15.4.1 The Origin of Metastatic CSCs 340
15.4.1.1 Cell Fusion and Metastatic CSCs 341
15.4.2 Do Organ-Specific Gene Signatures Point to the Existence of Organ-Specific mCSCs? 342
15.5 Cancer Relapse and CSCs 344
15.5.1 Oncogenic Resistance and Recurrence CSCs (rCSCs) 346
15.5.2 How Do rCSCs Originate? 346
15.5.3 Cell Fusion and rCSCs 348
15.6 Conclusions 352
References 354
16 Elimination of Cancer Stem Cells 360
16.1 The Cancer Stem Cell Hypothesis 361
16.2 The Failure of Conventional Cancer Therapies 362
16.3 Searching for a Valid Target: Knowledge of Stem Cell Biology 363
16.3.1 Self-renewal 363
16.3.2 Differentiation Potential 364
16.3.3 Quiescence/Long-Life 364
16.3.4 Metastasis 365
16.3.5 Migration 366
16.3.6 Transplantation 366
16.4 Therapeutic Approaches Against Cancer Stem Cells: Eliminating CSCs 366
16.4.1 Differentiation Therapies 368
16.4.2 Destruction Therapies 368
16.4.2.1 Targeted Therapy Against Self-renewal Signaling Pathways 368
16.4.2.2 Modulation of Chemoresistance Mechanisms 376
16.4.2.3 Others Mechanism Affecting CSCs or Their Niche 378
16.5 Imaging CSCs 380
16.6 Future Prospects 381
References 382
17 Potential Molecular Therapeutic Targets in Cancer Stem/Progenitor Cells: Are ATP-Binding Cassette Membrane Transporters Appropriate Targets to Eliminate Cancer-Initiating Cells? 388
17.1 Introduction 389
17.2 Phenotypic and Functional Properties of Cancer Stem/Progenitor Cells 390
17.3 Intrinsic Properties Associated with the Treatment Resistance of Cancer Stem/Progenitor Cells 391
17.3.1 Structures of ABC Transporters and Their Functions in Multidrug Resistance 392
17.3.2 Therapeutic Strategies for Overcoming ABC Transporter-Mediated MDR 395
17.3.2.1 Inhibitors of ABC Transporters 395
17.3.2.2 Modulatory Agents of the Transduction Signaling Elements Involved in the Regulation of ABC Transporter Expression and Functions 397
17.4 Implications of Cancer Stem/Progenitor Cells in Cancer Development, Treatment Resistance and Potential Molecular Therapeutic Targets 398
17.4.1 Functions of Leukemic Stem/Progenitor Cells in Leukemias and Potential Therapeutic Targets 398
17.4.1.1 Molecular Therapeutic Targets in AML and APL 399
17.4.1.2 Molecular Therapeutic Targets in CML 401
17.4.1.3 Stem Cell-Based Transplantation Therapies 402
17.4.2 Functions of Melanoma Stem Cells in Cutaneous Melanoma and Potential Therapeutic Targets 403
17.4.3 Functions of Brain Tumor Stem Cells in Brain Cancers and Potential Therapeutic Targets 404
17.4.4 Functions of Tumorigenic Stem/Progenitor Cells in Epithelial Cancers and Potential Therapeutic Targets 406
17.4.4.1 New Therapies Against Epithelial Cancers by Molecular Targeting of Tumorigenic and Migrating Cancer Stem/Progenitor Cells and Their Progenies 407
17.5 Conclusions and Perspectives 410
References 411
Index 425