Medical Applications of iPS Cells: Innovation in Medical Sciences (Current Human Cell Research and Applications)

This volume highlights recent advances using iPS cells in disease modeling and medical applications along with new technologies that enhance the power of iPS cells. While the discovery of iPS cells has provided excellent opportunities for developing models of human diseases, platforms for drug discovery and cell therapies, iPS cell technology still faces many challenges. Presenting the latest advances in this rapidly evolving research area, this book is intended to widen the community of researchers and clinicians interested in the exciting field of iPS cells. -- Provided by publisher Preface 6 Acknowledgments 8 Contents 9 Part I: Introduction 11 Chapter 1: Clinical Potential of Induced Pluripotent Stem Cells 12 1.1 Clinical Applications of iPSCs 13 1.2 Obstacles to Clinical Application 17 1.3 Conclusion 18 References 19 Part II: Disease Modelling 22 Chapter 2: Disease Modeling of Hematological and Immunological Disorders Using Induced Pluripotent Stem Cells 23 2.1 Introduction 23 2.2 Hematopoietic Differentiation for Disease Modeling 24 2.3 Disease Modeling of Hematopoietic Disorders with iPSCs 25 2.4 Disease Modeling of Immunological Disorders with iPSCs 27 2.5 In Vitro Modeling of Gene Therapy Using iPSCs 29 2.6 Conclusion 30 References 30 Chapter 3: iPS Cell Technology for Dissecting Cancer Epigenetics 36 3.1 Epigenetic Alterations in Cancer 37 3.2 Cause of Epigenetic Alterations in Cancer 39 3.2.1 Gene Mutations at Epigenetics-Related Genes 39 3.2.2 Environmental Factor-Mediated Modulation of Epigenetic Landscape 40 3.3 Relationship Between Reprogramming and Cancer Development 41 3.4 Application of Reprogramming Technologies for Cancer Research 42 3.4.1 Cancer Cell Reprogramming 42 3.4.2 Cell-Type-Specific Carcinogenesis 42 3.4.3 Recapitulation of Human Cancer Progression In Vivo 44 3.4.4 Hierarchy of Heterogeneous Cancer Cells 44 3.5 Cancer Research Using In Vivo Reprogramming Technology 45 3.6 Technical Problems in the Application of Reprogramming Technology to Cancer Research 46 3.7 Future Perspective 47 References 47 Chapter 4: Recapitulating Hematopoietic Development in a Dish 51 4.1 Introduction 52 4.2 Mapping In Vivo Hematopoiesis to Direct In Vitro Blood Cell Development 53 4.2.1 Primitive Wave (Yolk Sac) Hematopoietic Development 53 4.2.2 Erythro-myeloid Progenitor (EMP) Hematopoiesis 53 4.2.3 Lymphoid-Primed Multipotent Progenitor (LMPP) Hematopoiesis 55 4.2.4 Definitive Wave (AGM) Hematopoietic Development 55 4.2.4.1 Hemogenic Endothelium and Endothelial-to-Hematopoietic Transition 56 4.2.4.2 Origins of the Hematopoietic Stem Cell 56 4.2.5 Identification and Characterization of Primitive Versus Definitive Wave Hematopoiesis 57 4.2.5.1 Using Globin Expression to Identify Subsequent Hematopoietic Programs 57 4.3 In Vitro Hematopoiesis Through the Lens of a Pluripotent Stem Cell Model 58 4.3.1 In Vitro Recapitulation of Successive Hematopoietic Programs 59 4.3.2 Endothelial-to-Hematopoietic Transition (EHT) in the Dish 61 4.3.3 Engineering Hematopoietic Stem Cells from Pluripotent Stem Cells 61 4.3.3.1 In Vivo Differentiation Through Teratoma Formation: The Mouse as Incubator 62 4.3.3.2 Induction of an HSC Program Through Forced Expression of Exogenous Factors 63 4.3.4 Initiation of Globin Switching in PSC-Derived Erythroid-Lineage Cells 64 4.4 Harnessing iPSCS for Hematological Disease Modeling and Drug Discovery 64 4.4.1 Hematological Disorders Affecting Hematopoietic Stem and Progenitor Cells (HSPCs) 65 4.4.2 Hemoglobinopathies: From Gene Correction and Disease Modeling to Drug Discovery and Validation in a Patient-Specific Genetic Context 66 4.5 Conclusion 68 References 69 Chapter 5: Modeling Cardiomyopathies with iPSCs 78 5.1 Introduction 78 5.2 Modeling Genetic Cardiac Arrhythmias 80 5.2.1 Congenital Long QT Syndrome 80 5.2.1.1 Long QT Type 1 81 5.2.1.2 Long QT Type 2 82 5.2.1.3 Long QT Type 3 83 5.2.1.4 Long QT Type 7 or Andersen-Tawil Syndrome 83 5.2.1.5 Long QT Type 8 or Timothy Syndrome 83 5.2.1.6 Long QT Type 15 or Calmodulinopathies 84 5.2.1.7 Jervell and Lange-Nielsen Syndrome 84 5.2.2 Catecholaminergic Polymorphic Ventricular Tachycardia 84 5.2.3 Brugada Syndrome 85 5.3 Modeling Genetic Cardiomyopathies 85 5.3.1 Dilated Cardiomyopathy (DCM) 89 5.3.1.1 Sarcomeric Proteins 89 5.3.1.2 Calcium Handling Proteins 89 5.3.1.3 Other Proteins 90 5.3.2 Hypertrophic Cardiomyopathy (HCM) 90 5.3.3 Other Cardiomyopathies 90 5.4 Modeling Metabolic Cardiomyopathy 91 5.4.1 Diabetic Cardiomyopathy 91 5.4.2 Barth Syndrome 91 5.4.3 Pompe Disease 91 5.4.4 Fabry Disease 92 5.5 Modeling Drug Responses in iPSC-Derived Cardiomyocytes 92 5.5.1 Pharmacological Testing in Diseased iPSC-Derived Cardiomyocytes 92 5.5.2 Cardiovascular Pharmacogenomics 93 5.6 Future Developments and Conclusions 94 References 95 Part III: Molecular Technologies 101 Chapter 6: Endogenous Signal-Responsive Transgene Switch Systems for Visualization and Purification of Specific Cells 102 6.1 Introduction 102 6.2 Visualization of Differentiation States and Purification of Specific Cells Using Fluorescent Protein Expression Switches 103 6.2.1 Endogenous Protein-Responsive Switches that Regulate Fluorescent Protein Expression 103 6.2.2 miRNA-Responsive Fluorescent Protein Expression Switch 104 6.3 Elimination of Undesired Cells Using Cell-Specific Killing Switches 108 6.3.1 Elimination of miRNA-Positive Cells Using an Antibiotic Gene Expression Switch 108 6.3.2 Elimination of miRNA-Negative Cells Using Apoptosis-Inducing Gene Expression Switches 108 6.4 Cell-Selective Genome Editing 109 6.5 Design and Preparation of Suitable Switches 110 6.6 Conclusion and Future Perspective 113 References 114 Chapter 7: Precision Genome Editing in Human-Induced Pluripotent Stem Cells 116 7.1 Introduction 116 7.2 Creating Genomic DSBs 117 7.3 Repairing Genomic DSBs 119 7.4 Modulation of DSBR 121 7.5 Delivery of Nucleases to hiPSCs 121 7.6 Enriching for Desirable Gene Editing Events 122 7.7 Precise Removal of Selection Markers 124 7.8 Considering Individuality in hiPSCs Genome Editing 126 7.9 Conclusions 127 References 127 Part IV: iPS Applications 134 Chapter 8: Induced Pluripotent Stem Cell-Based Cell Therapy of the Retina 135 8.1 Introduction 136 8.2 Neural Stem Cells for Retinal Regenerative Medicine 136 8.3 RPE Replacement Therapies for Age-Related Macular Degeneration 137 8.3.1 Role of the RPE 137 8.3.2 Treatment Concept 138 8.3.3 ESCs as a Source for RPE 138 8.3.4 iPSC as a Source for RPE 139 8.3.5 Superiority of iPSC-RPE for Transplantation 140 8.3.6 Production of iPSC-RPE for Its Clinical Application 140 8.3.7 First Clinical Application of iPSC for AMD 141 8.3.8 Allotransplantation Using iPSC-RPE 142 8.4 ESC/iPSC-Photoreceptor Replacement Therapy 143 8.4.1 Target Disease for Photoreceptor Replacement Therapy 143 8.4.2 Treatment Concept of Retina or Photoreceptor Transplantation 143 8.4.3 Photoreceptors Generated from Stem Cells 144 8.4.4 Treatment Proof of Concept 144 8.4.5 Environmental Factors Supporting Retinal Graft Survival 145 8.5 Conclusion 145 References 146 Chapter 9: Organoid Models of Development and Disease Towards Therapy 150 9.1 Introduction 151 9.1.1 Historical Developments in Tissue Organoids (3D Models for Organ Development) 151 9.1.1.1 First (Organoid 1.0): Reaggregation and Self-Organization 151 9.1.1.2 Second (Organoid 2.0): Laminin-Rich Basement Membrane Matrix (BM) 151 9.1.1.3 Third (Organoid 3.0): Human Stem Cells 153 9.2 Tissue Organoids 153 9.2.1 Liver Organoids 153 9.2.2 Brain Organoids 154 9.2.3 Retinal Organoids 155 9.2.4 Kidney Organoids 156 9.2.5 Intestinal Organoids 156 9.2.6 Stomach Organoids 157 9.2.7 Pancreas Organoids 157 9.2.8 Lung Organoids 158 9.3 3D Organoids for Disease Treatment 159 9.3.1 Introduction 159 9.3.2 3D Models for Drug Discovery 159 9.3.2.1 Spheroid-Based Drug Screening 159 9.3.2.2 Organotypic Culture- and Organoid-Based Drug Screening 160 9.3.2.3 Organoid-Based Toxicology Study 161 9.3.3 Challenges, Limitations, and Future Perspectives for 3D Cell Cultures 162 9.3.4 Emerging Approaches 163 9.4 Conclusion 164 References 165 Chapter 10: In Vivo Cell Conversion as a New Cell Therapy 170 10.1 Classical Cell Therapy for Neural Repair 171 10.2 In Vivo Cell Conversion as the Next-Generation Cell Therapy 173 10.3 Pancreas 173 10.4 Heart 174 10.5 Liver 176 10.6 In Vivo Cell Conversion in the CNS 176 10.7 Cerebral Cortex 177 10.8 Striatum 178 10.9 Spinal Cord 179 10.10 Retina 180 10.11 Conclusion and Perspective 181 References 182 Front Matter ....Pages i-x Front Matter ....Pages 1-1 Clinical Potential of Induced Pluripotent Stem Cells (Peter Karagiannis)....Pages 3-12 Front Matter ....Pages 13-13 Disease Modeling of Hematological and Immunological Disorders Using Induced Pluripotent Stem Cells (Megumu K. Saito)....Pages 15-27 iPS Cell Technology for Dissecting Cancer Epigenetics (Hirofumi Shibata, Yasuhiro Yamada)....Pages 29-43 Recapitulating Hematopoietic Development in a Dish (Kim Vanuytsel, Martin H. Steinberg, George J. Murphy)....Pages 45-71 Modeling Cardiomyopathies with iPSCs (Jean-Sébastien Hulot)....Pages 73-95 Front Matter ....Pages 97-97 Endogenous Signal-Responsive Transgene Switch Systems for Visualization and Purification of Specific Cells (Hideyuki Nakanishi, Hirohide Saito)....Pages 99-112 Precision Genome Editing in Human-Induced Pluripotent Stem Cells (Knut Woltjen)....Pages 113-130 Front Matter ....Pages 131-131 Induced Pluripotent Stem Cell-Based Cell Therapy of the Retina (Seiji Takagi, Michiko Mandai, Yasuhiko Hirami, Yasuo Kurimoto, Masayo Takahashi)....Pages 133-147 Organoid Models of Development and Disease Towards Therapy (Yasunori Nio, Takanori Takebe)....Pages 149-168 In Vivo Cell Conversion as a New Cell Therapy (Hedong Li, Lei Zhang, Yuchen Chen, Zheng Wu, Zhuofan Lei, Gong Chen)....Pages 169-190