Stem Cell Therapy for Diabetes (eBook)

Preface 4
Contents 6
Contributors 8
Part I Beta-Cell Expansion and Regeneration 11
1 Pancreas and Islet Development 12
1.1 Basic Pancreas Embryology and Development of Pancreatic Endocrine Cells 12
1.2 Early Tissue Interactions 14
1.2.1 Notochord 14
1.2.2 Endothelium 15
1.2.3 Mesenchyme 15
1.3 Soluble Factors and Signaling Pathways Regulating Pancreas Development 16
1.3.1 Fibroblast Growth Factors (FGFs) 17
1.3.2 Transforming Growth Factor (TGF-) 17
1.3.2.1 TGF- Isoforms 17
1.3.2.2 Activins and BMPs 18
1.3.2.3 Growth Differentiation Factor 11 (GDF11) 20
1.3.3 NOTCH Signaling 20
1.3.4 Hedgehog Signaling 21
1.3.5 Retinoids 21
1.3.6 Epidermal Growth Factor (EGF) Family 22
1.3.7 Hepatocyte Growth Factor (HGF) 23
1.3.8 WNT Signaling 23
1.3.9 Blood Vessel- and Endothelial-Derived Factors 24
1.3.10 Glucagon-Family (and Other Peptide Hormones) Signaling 25
1.3.11 Extracellular Matrix and Cell Adhesion Molecules 26
1.3.12 Other Extracellular Molecules 26
1.4 Transcription Factors Regulating Pancreas Development 27
1.4.1 PDX1 29
1.4.2 PBX1 31
1.4.3 PTF1A 31
1.4.4 NGN3 32
1.4.5 NEUROD 33
1.4.6 PAX6 33
1.4.7 PAX4 and ARX 33
1.4.8 NKX2.2 34
1.4.9 NKX6.1 and NKX6.2 34
1.4.10 MAFA and MAFB 35
1.4.11 HNF Cascade 35
1.4.12 SOX9 36
1.4.13 MYT1, GATA Factors, HB9, SOX4, ISL1, HEX, PROX1, and BRAIN4 36
1.5 MicroRNAs 37
1.6 Summary 38
References 38
2 Islet and Pancreas Transplantation 50
2.1 Type 1 Diabetes Mellitus 50
2.2 Pancreatic Islet Allotransplantation 51
2.2.1 Islet Transplantation Procedures 52
2.2.1.1 Recipient and Donor Selection 52
2.2.1.2 Pancreas Procurement, Islet Isolation, and Transplantation 53
2.2.2 Clinical Protocols 56
2.2.2.1 Historical Protocols 56
2.2.2.2 Current Protocols 58
2.2.3 Results 61
2.2.3.1 Clinical Outcomes 61
2.2.3.2 Islet Graft Monitoring 65
2.2.4 Complications and Limitations 66
2.2.4.1 Recipient- and Graft-Related Complications 66
2.2.4.2 Transplant-Related Limitations 69
2.2.4.3 Current Challenges and Future Perspectives 70
2.2.5 Conclusions 71
2.3 Simultaneous PancreasKidney Transplantation 71
2.3.1 Clinical Protocols 72
2.3.1.1 Maintenance Immunosuppression 72
2.3.1.2 Induction Therapy 73
2.3.2 Results 76
2.3.2.1 Patient and Graft Survival 76
2.3.2.2 Diabetic Nephropathy 76
2.3.2.3 Diabetic Retinopathy 77
2.3.2.4 Diabetic Neuropathy 77
2.3.2.5 Quality of Life 78
2.3.3 Complications and Limitations 78
2.3.3.1 Hypercoagulation in SPK 78
2.3.3.2 Bladder-Drained Pancreas Transplant 80
2.3.3.3 Enteric-Drained Pancreas Transplant 81
2.3.4 Conclusions 82
References 82
3 Cell Cycle Regulation in Human Pancreatic Beta Cells 93
3.1 Introduction 93
3.2 Differences between Human and Rodent Beta Cells 95
3.3 Embryonic and Neonatal Human Beta Cells Can Replicate 96
3.4 Evidence for Limited Replication of Adult Human Beta Cells 97
3.5 Attempts to Engineer Beta-Cell Replication 98
3.6 Components of the Human Islet G1/S Transition Proteome 99
3.7 Interpretation of Human Beta-Cell Cycle Activation by CDK6 and Cyclin D 1 103
3.8 Cell Cycle Inhibitors in Human Beta Cells 104
3.9 Epigenetic Changes in Beta-Cell Cycle Control 105
3.10 Future Therapeutic Directions in Human Beta-Cell Cycle Control 105
3.11 Conclusions 107
References 108
4 Islet Regeneration 112
4.1 Introduction 112
4.2 Measuring Islet Regeneration 113
4.3 Experimental Models for Inducing Beta-Cell Regeneration 113
4.3.1 Beta-Cell Ablation by Toxins 114
4.3.2 Surgical Methods for Inducing Pancreas Injury 115
4.3.3 Genetic Ablation of Beta Cells 117
4.4 Islet Regeneration: Proliferation and/or (Trans)Differentiation? 118
4.4.1 Proliferation of Preexisting Beta Cells 119
4.4.2 Differentiation of Pancreatic Progenitor Cells 120
4.4.3 Transdifferentiation from Pancreatic Exocrine Cells 123
4.5 Effects of Cell Microenvironment: The Niche that Allows Beta-Cell Mass Expansion 123
References 124
5 Beta-Cell Expansion in Vitro 130
5.1 Beta-Cell Replication in Vivo 130
5.2 Beta-Cell Replication in Vitro 131
5.3 Lineage-Tracing of Cultured Human Beta Cells 133
5.4 Redifferentiation of Cells Expanded from Human Beta Cells 134
5.5 Signaling Pathways Involved in Ex-Vivo Human Beta-Cell Dedifferentiation and Replication 136
5.6 Future Prospects 137
References 138
Part II Beta Cells from Non-beta Cells 141
6 What Does It Take to Make a Beta Cell? 142
6.1 The Advantageous Anatomic Location of Beta Cells 142
6.2 Islet Blood Flow and the Relationship between Islet Cell Types 143
6.3 Why Are Islets Distributed throughout the Pancreas in Mammals? 146
6.4 A Dominant Role for Beta Cells in Maintaining Blood Glucose Homeostasis 146
6.5 Phenotype of the Typical Beta Cell 146
6.6 Beta-Cell Turnover and Heterogeneity 148
6.7 Insulin Secretion in Normal Physiological Conditions 148
6.8 Does the Normal Relationship among Beta Cells, Non-beta Cells, and Blood Vessels Have to Be Reestablished in a Graft Site? 149
6.9 How Large Should Islets Be for Optimal Transplantation? 150
6.10 How Good Must a Beta Cell Be to Succeed When Transplanted? 151
6.11 Testing to Determine How Close Insulin-Producing Cells Are to Normal Beta Cells 152
6.12 Summary 154
References 154
7 Generation of Beta Cells from Acinar Cells 158
7.1 Introduction 158
7.2 In-Vitro Dedifferentiation of Acinar Cells 160
7.3 In-Vitro Transdifferentiation of Acinar Cells into Beta Cells 163
7.4 Mechanism of Acinar-to-Beta-Cell Transdifferentiation 164
7.5 Phenotype and Function of Beta Cells Generated from Acinar Cells 166
7.6 Translation to the Clinic 167
7.7 Future Work 167
References 168
8 Generation of Beta Cells from Pancreatic Duct Cells and/or Stem Cells 172
8.1 Introduction 172
8.2 Definition of Terms 173
8.3 Are There Pancreatic Stem Cells? 174
8.4 In-Vitro Evidence of Pancreatic Progenitors in Ducts 176
8.4.1 Progenitors in Human Pancreatic Duct-Enriched, Islet-Depleted Tissue 176
8.4.2 Progenitors in Mouse Pancreas Ductal Cells 177
8.5 In-Vivo Evidence of Postnatal Pancreatic Progenitors 179
8.5.1 Insulin Promoter-Interferon Transgenic Mice 179
8.5.2 Metallothionein-TGF Transgenic Mice 180
8.5.3 Partial (90 0 ) Pancreatectomized Rats 180
8.5.4 Ductal Ligation 181
8.6 How Large Is the Contribution of Neogenesis to Islet Mass? 182
8.7 Is There a Population of Multipotent Progenitor/Stem Cells that Are Activated as Needed? 183
References 183
9 Adult Cell Reprogramming: Using Nonpancreatic Cell Sources to Generate Surrogate Beta Cells for Treatmentof Diabetes 188
9.1 Adult Cell Reprogramming 188
9.2 Conversion of Liver Cells into Pancreas Cells 189
9.2.1 The Rationale for Using Liver as a Source for Pancreatic Tissue 190
9.2.2 Reprogramming Liver Cells Using Ectopic Expression of Pancreatic Transcription Factors 190
9.2.2.1 In-Vitro Reprogramming of Embryonic or Fetal Liver Cells 191
9.2.2.2 In-Vitro Reprogramming of Adult Rodent and Human Liver Cells 192
9.2.2.3 In-Vivo Reprogramming of Adult Xenopus and Rodent Liver Cells 193
9.2.3 Liver-to-Pancreas Transdifferentiation Involves Hepatic Dedifferentiation 196
9.2.4 Which Is the Vector of Choice for Inducing Liver Transdifferentiation into Beta Cells? 197
9.2.5 Optimizing Transcription Factor-Induced Transdifferentiation of Liver into Beta Cells 198
9.2.5.1 PDX1 Fusion with VP16 198
9.2.5.2 Using Combinations of Pancreatic Transcription Factors 199
9.2.5.3 Using Soluble Factors to Promote Transcription-Factor-Induced Liver-to-Pancreas Transdifferentiation 200
9.3 Conversion of Bone-Marrow-Derived Mesenchymal Stem Cells into Pancreas Cells 201
9.4 From the Bench to Bedside: Challenges in Using Adult Cell Reprogramming in Regenerative Medicine 202
References 203
10 Embryonic Stem Cells as a Potential Cure for Diabetes 208
10.1 Introduction 208
10.2 The Embryonic Stem Cell State Is Unique 209
10.3 Embryonic Stem Cells Are in a Constitutively Proliferative State 211
10.4 Directed Differentiation of Embryonic Stem Cells: Seeking Sanity in the Midst of Chaos 212
10.5 Progress in Making Beta Cells from hES Cells 213
10.5.1 Stage 1: Definitive Endoderm Formation 214
10.5.2 Stage 2: Foregut Endoderm Formation 215
10.5.3 Stage 3: Pancreatic Determination 216
10.5.4 Stage 4 and Beyond: Islet Cell Maturation 216
10.5.5 A Consideration of Time 217
10.6 Challenges of Directed Differentiation of ES Cells into Beta Cells 218
10.7 Other Issues that Have to be Resolved before Transplantation 220
10.8 Adult Cellular Makeover: Somatic-to-Somatic Cell Reprogramming 221
10.9 Conclusion 221
References 222
Part III Tissue Engineering and Immune Protection 226
11 Functional Tissue Reconstruction with the Use of BiologicScaffolds 227
11.1 Introduction 227
11.2 Composition of Biologic Scaffold Materials 228
11.3 Structure of ECM Biologic Scaffold Materials 229
11.4 Preparation of ECM Scaffolds and Its Effects upon Structure and Function 230
11.4.1 Decellularization 231
11.4.2 Hydration 231
11.4.3 Dehydration 232
11.4.4 Powdered ECM Scaffolds 233
11.4.5 Gelation of ECM Scaffolds 233
11.5 Bioactive Properties of ECM Scaffolds 233
11.6 Culture and Transplantation of Pancreatic Islet Cells on ECM s 234
11.7 Lessons from Adrenocortical Cells Grown on Native Adrenal ECM 236
11.8 Summary 237
References 238
12 Immunoisolation in Cell Transplantation 244
12.1 Encapsulation of Live Cells/Tissue: Definition, Scope, and Applications 244
12.2 Biomaterials for Microencapsulation 245
12.2.1 Macrodevices 246
12.2.2 Microcapsules 248
12.2.2.1 Agarose 248
12.2.2.2 Polyethylene Glycol 249
12.2.2.3 Chitosan 249
12.2.2.4 Hydroxyethyl-Methacrylate-Methyl-Methacrylate (HEMA-MMA) 250
12.3 Alginate-Based Microcapsules 250
12.3.1 Alginate Production and Use 250
12.3.2 Morphology and Size of Alginate Microcapsules 252
12.3.2.1 Conventional Microcapsules 252
12.3.2.2 Conformal Microcapsules 254
12.3.2.3 Capsule Biocompatibility 254
12.3.3 Encapsulation of Alternatives to Human Islets 256
12.4 Immunology of Microencapsulated Cell Transplants 258
12.4.1 Immune Responses Activated by the Transplant 258
12.4.2 Complementary Immunoprotection Strategies 258
12.5 In-Vivo Applications 259
12.5.1 Experimental Systems 259
12.5.2 Pilot Human Clinical Trials Using Microencapsulated Islet Allografts in Patients with T1DM 260
12.6 Summary and Future Perspectives 261
References 262
13 Prevention of Islet Graft Rejection and Recipient Tolerization 266
13.1 Introduction 266
13.2 The Immunological Process in T1DM 267
13.2.1 Cellular and Humoral Mediators of Beta-Cell Destruction 267
13.2.1.1 The Role of T Cells in T1DM 267
13.2.1.2 The Role of B Cells in T1DM 269
13.2.2 The Role of Costimulatory Molecules in Activating Auto- and Alloreactive Immune Responses 270
13.3 Mechanisms of Islet Transplant Failure in T1DM 272
13.4 Tolerance Induction and Prolongation of Islet Survival 273
13.4.1 The Use of Anti-Inflammatory Agents for Induction of Islet Tolerance 273
13.4.2 Barriers to Long-Term Success 275
13.5 Summary and Conclusions 275
References 277
Index 283