細胞治療：技術・市場・企業

Abstract

Summary

This report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine. Hematopoietic stem cell transplantation is replacing the old fashioned bone marrow transplants. Role of cells in drug discovery is also described. Cell therapy is bound to become a part of medical practice.

Stem cells are discussed in detail in one chapter. Some light is thrown on the current controversy of embryonic sources of stem cells and comparison with adult sources. Other sources of stem cells such as the placenta, cord blood and fat removed by liposuction are also discussed. Stem cells can also be genetically modified prior to transplantation.

Cell therapy technologies overlap with those of gene therapy, cancer vaccines, drug delivery, tissue engineering and regenerative medicine. Pharmaceutical applications of stem cells including those in drug discovery are also described. Various types of cells used, methods of preparation and culture, encapsulation and genetic engineering of cells are discussed. Sources of cells, both human and animal (xenotransplantation) are discussed. Methods of delivery of cell therapy range from injections to surgical implantation using special devices.

Cell therapy has applications in a large number of disorders. The most important are diseases of the nervous system and cancer which are the topics for separate chapters. Other applications include cardiac disorders (myocardial infarction and heart failure), diabetes mellitus, diseases of bones and joints, genetic disorders, and wounds of the skin and soft tissues.

Regulatory and ethical issues involving cell therapy are important and are discussed. Current political debate on the use of stem cells from embryonic sources (hESCs) is also presented. Safety is an essential consideration of any new therapy and regulations for cell therapy are those for biological preparations.

The cell-based markets was analyzed for 2008, and projected to 2018.The markets are analyzed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair as well as diabetes mellitus will be other major markets.

The number of companies involved in cell therapy has increased remarkably during the past few years. More than 500 companies have been identified to be involved in cell therapy and 256 of these are profiled in part II of the report along with tabulation of 241 alliances. Of these companies, 138 are involved in stem cells. Profiles of 62 academic institutions in the US involved in cell therapy are also included in part II along with their commercial collaborations. The text is supplemented with 44 Tables and 11 Figures. The bibliography contains 750 selected references, which are cited in the text.

Table of Contents

0. Executive Summary 21

1. Introduction to Cell Therapy 25

• Introduction 25
• Historical landmarks of cell therapy 25
• Interrelationship of cell therapy technologies 27
• Cells and organ transplantation 27
• Cells and protein/gene therapy 28
• Cell therapy and regenerative medicine 29
• Cells therapy and tissue engineering 29
• Therapy based on cells involved in disease 30
• Advantages of therapeutic use of cells 30
• Use of cells for improving drug delivery 31

2. Cell Therapy Technologies 33

• Introduction 33
• Cell types used for therapy 33
• Sources of cells 33
• Xenografts 34
• Cell lines 34
• Immortalized cells 34
• Blood component therapy 34
• Therapeutic apheresis 34
• Leukoreduction 35
• Platelet therapy 35
• Basic technologies for cell therapy 36
• Cell culture 36
• Observation of stem cell growth and viability 36
• Companies involved in cell culture 36
• Cell sorting 38
• Flow cytometry 38
• A dieltectrophoretic system for cell separation 39
• Molecular beacons for specific detection and isolation of stem cells 39
• Multitarget magnetic activated cell sorter 39
• Companies supplying cell sorters 40
• Dynabead technology for cell sorting 41
• ALDESORTER system for isolation of stem cells 41
• Cell analysis 41
• Preservation of cells 42
• Innovations in cryopreservation 42
• Packaging of cells 42
• Selective expansion of T cells for immunotherapy 43
• Cloning and cell therapy 44
• Techniques for cell manipulation 44
• Cell-based drug discovery 44
• Cells as vehicles for drug delivery 47
• Drug delivery systems for cell therapy 47
• Intravenous delivery of stem cells 47
• Pharmacologically active microcarriers 48
• Devices for delivery of cell therapy 48
• Artificial cells 49
• Applications of artificial cells 49
• Cell encapsulation 50
• Diffusion capsule for cells 50
• Encapsulated cell biodelivery 51
• Therapeutic applications of encapsulated cells 51
• Nitric oxide delivery by encapsulated cells 52
• Implantation of microencapulated genetically modified cells 53
• Ferrofluid microcapsules for tracking with MRI 53
• Companies involved in encapsulated cell technology 54
• Electroporation 54
• Gene therapy 55
• Cell-mediated gene therapy 55
• Fibroblasts 55
• Chondrocyte 56
• Skeletal muscle cells 57
• Vascular smooth muscle cells 57
• Keratinocytes 57
• Hepatocytes 58
• Lymphocytes 58
• Mammalian artificial chromosomes 58
• In vivo tracking of cells 58
• Molecular imaging for tracking cells 59
• MRI technologies for tracking cells 59
• Superparamagnetic iron oxide nanoparticles as MRI contrast agents 60
• Visualization of gene expression in vivo by MRI 60
• Role of nanobiotechnology in development of cell therapy 61
• Cell transplantation for development of organs 61
• Cells transplantation and tolerance 62
• Strategies to improve tolerance of transplanted cells 62
• Encapsulation to prevent immune rejection 62
• Prevention of rejection of xenotransplants 62
• Removal and replacement of pathogenic cells of the body 63
• Therapeutic leukocytapheresis 63

3. Stem Cells 65

• Introduction 65
• Biology of stem cells 66
• Embryonic stem cells 66
• Growth and differentiation of ESCs 66
• Regulation of stem cell self-renewal and differentiation 67
• Role of Pax3 in stem cell differentiation 67
• ESCs and signaling pathways 68
• Genetic signature of of stem cells 68
• Epigenetics of hESCs 68
• Chromatin as gene regulator for ESC development 69
• Mechanism of differentiation of ESCs 69
• Chemical regulation of stem cell differentiation 70
• Comparison of development of human and mouse ESCs 70
• In vitro differentiation of hESCs 70
• Global transcription in pluripotent ESCs 71
• Signaling pathways and transcription factors in ESCs 71
• Stem cells in the pituitary gland 71
• hESCs in stead of oocytes for reprogramming human somatic nuclei 72
• Mechanism of regulation of stem cells for regeneration of body tissues 72
• Role of microenvironments in the regulation of stem cells 72
• Regulation and regeneration of intestinal stem cells 73
• Parthenogenesis and human stem cells 73
• Uniparental ESCs 74
• Bone marrow stem cells 74
• Hematopoietic stem cells 74
• Role of HSCs in the immune system 76
• Derivation of HSCs from ESCs 76
• Mesenchymal stem sells 77
• Multipotent adult progenitor cells 78
• Side population (SP) stem cells 78
• Differentiation of adult stem cells 79
• Growth and differentiation of HSCs 80
• Signaling pathways in the growth and differentiation of HSCs 80
• Mathematical modeling of differentiation of HSCs 80
• Role of prions in self renewal of HSCs 81
• Sources of stem cells 81
• Sources of of human embryonic stem cells 81
• Nuclear transfer to obtain hESCs 82
• Direct derivation of hESCs from embryos without nuclear transfer 83
• Alternative methods of obtaining hESCs 83
• Establishing hESC lines without destruction of embryo 83
• Altered nuclear transfer 84
• Small embryonic-like stem cells 85
• Advantages and disadvantages of ESCs for transplantation 85
• Use of ESC cultures as an alternative source of tissue for transplantation 85
• Spermatogonial stem cells 86
• Amniotic fluid as a source of stem cells 87
• Placenta as source of stem cells 87
• Amnion-derived multipotent progenitor cells 87
• Placenta as a source of HSCs 88
• Umbilical cord perivascular cells as a source of MSCs 88
• Umbilical cord blood as source of neonatal stem cells 88
• Cryopreservation of UCB stem cells 89
• UCB as source of MSCs 90
• Applications of UCB 90
• Advantages of UCB 90
• Limitations of the use of UCB 91
• Licensing and patent disputes involving UCB 92
• Infections following UCB transplants 92
• Unanswered questions about umbilical cord blood transplantation 93
• Companies involved in umbilical cord blood banking 93
• UCB banking in the UK 94
• US national UCB banking system 95
• Future prospects of UCB as a source of stem cells 96
• Sources of adult human stem cells 96
• Adipose tissue as a source of stem cells 97
• Skin as a source of stem cells 97
• Follicle stem cells 98
• Mesenchymal stem cells in skin 98
• Epidermal neural crest stem cells 99
• Regulation of stem cells in hair follicles 99
• Controlling the maturation of embryonic skin stem cells 99
• Stem cells in teeth 100
• Peripheral blood stem cells 100
• Spleen as a source of adult stem cells 101
• Search for master stem cells 101
• Adult stem cells vs embryonic stem cells 102
• Transdifferentiation potential of adult stem cells 102
• Neural crest stem cells from adult hair follicles 103
• Stem cells obtained from blood in adults 104
• Pluripotent stem cells derived from human somatic cells 104
• Use of retroviral vectors for generation of induced pluripotent cells 104
• Use of non-integrating viral vectors for generation of induced pluripotent cells 105
• VENT cells 106
• Stem cell technologies 106
• Analysis of stem cell growth and differentiation 106
• Tracking self-renewal and expansion of transplanted muscle stem cells 106
• Stem cell biomarkers 107
• Endoglin as a functional biomarker of HSCs 107
• STEMPRO® EZChek™ for analysis of biomarkers of hESCs 107
• SSEA-4 as biomarker of MSCs 108
• p75NTR as a biomarker to isolate adipose tissue-derived stem cells 108
• Neural stem cell biomarker 108
• Protein expression profile as biomarker of stem cells 109
• Gene inactivation to study hESCs 109
• RNAi to study gene inactivation in hESCs 109
• Study of ESC development by inducible RNAi 110
• Targeting Induced Local Lesions in Genomes 110
• Homologous recombination of ESCs 110
• Immortalization of hESCs by telomerase 111
• miRNA and stem cells 111
• Role of miRNAs in gene regulation during stem cell differentiation 111
• Influence of miRNA on stem cell formation and maintenance 112
• Transcriptional regulators of ESCs control miRNA gene expression 112
• Stem cells and cloning 113
• Cell nuclear replacement and cloning 113
• Nuclear transfer and ESCs 113
• Cloning from differentiated cells 114
• Cloning mice from adult stem cells 115
• Creating interspecies stem cells 115
• Cloned cells for transplantation medicine 116
• Claims of cloning of hESCs 116
• Cytogenetics of embryonic stem cells 118
• Engraftment, mobilization and expansion of stem cells 118
• Adipogenesis induced by adipose tissue-derived stem cells 119
• Antisense approach for preservation and expansion of stem cells 119
• Enhancement of HSC engraftment by calcium-sensing receptor 120
• Enhancement of stem cell differentiation by Homspera 120
• Ex vivo expansion of human HSCs in culture 121
• Ex vivo expansion of MSCs 121
• Expansion of HSCs in culture by inhibiting aldehyde dehydrogenase 122
• Expansion of adult stem cells by activation of Oct4 122
• Expansion of transduced HSCs in vivo 122
• Mobilization of HSCs by growth factors 123
• Mobilization of stem cells by cytokines/chemokines 123
• Mobilization of adult human HSCs by use of inhibitors 124
• Mobilization of stem cells by HYC750 124
• Mobilization of stem cells by hyperbaric oxygen 125
• Mobilization by adenoviral vectors expressing angiogenic factors 125
• Selective mobilization of progenitor cells from bone marrow 125
• Selective Amplification 126
• Stem cell mobilization by acetylcholine receptor agonists 126
• Use of parathyroid hormone to increase HSC mobilzation 126
• Expansion of stem cells in vivo by Notch receptor ligands 127
• Technologies for inducing differentiation of stem cells 127
• Use of lineage selection to induce differentiation of hESCs 127
• Growth factor-induced differentiation of MAPCs 127
• Neurotrophin-mediated survival and differentiation of hESCs 127
• Generation of RBCs from hematopoietic stem cells 128
• Use of RNAi to expand the plasticity of autologous adult stem cells 128
• Use of carbohydrate molecules to induce differentiation of stem cells 129
• Mechanical strain to induce MSC differentiation 129
• Limitations of the currently available stem cell lines in the US 129
• Contaminating material in stem cell culture and measures to eliminate it 130
• Stem cell separation 131
• Stem cell culture 131
• Conversion of stem cells to functioning adipocytes 132
• Mass production of ESCs 132
• Promoting survival of dissociated hESCs 133
• Analysis and characterization of stem cells 133
• Labeling of stem cells 133
• Quantum dots for labeling hMSCs 134
• Imaging and tracking of stem cells in vivo 134
• Quantum dot imaging for ESCs 134
• Perfluorocarbon nanoparticles to track therapeutic cells in vivo 134
• Project for imaging in stem cell therapy research 135
• Applications of stem cells 135
• Controlling the maintenance process of hematopoietic stem cells 136
• Peripheral blood stem cell transplantation 136
• Complications of PBSC transplantation in children 136
• Stem cell transplantation for radiation sickness 137
• Stem cells and human reproduction 137
• Expansion of spermatogonial stem cells 137
• Conversion of ESCs into spermatogonial stem cells 137
• Conversion of stem cells to oocytes 138
• ESCs for treatment of infertility in women 138
• Cloning human embryos from oocytes matured in the laboratory 138
• In utero stem cell transplantation 139
• Innovations in delivery of stem cells 140
• Immunological aspects of hESC transplantation 140
• Immunosuppression to prevent rejection of hESC transplants 141
• Histocompatibility of hESCs 141
• Strategies for promoting immune tolerance of hESCs 141
• Stem cells for organ vascularization 142
• Activation of EphB4 to enhance angiogenesis by EPCs 143
• Biofusion by genetically engineering stem cells 143
• Stem cell gene therapy 143
• Combination of gene therapy with nuclear transfer 144
• Gene delivery to stem cells by artificial chromosome expression 144
• Genetic manipulation of ESCs 144
• HSCs for gene therapy 145
• Helper-dependent adenoviral vectors for gene transfer in ESCs 145
• Lentiviral vectors for in vivo gene transfer to stem cells 146
• Linker based sperm-mediated gene transfer technology 146
• Mesenchymal stem cells for gene therapy 146
• Molecular vibration for gene transfer 147
• Regulation of gene expression for SC-based gene therapy 147
• Stem cells and in utero gene therapy 147
• Therapeutic applications for hematopoietic stem cell gene transfer 148
• The future of hematopoietic stem cell gene therapy 148
• Stem cell pharmaceutics 148
• Stem cells for drug discovery 148
• Advantages of using stem cells for drug discovery 149
• Role of stem cells in therapeutic effects of drugs 149
• Hepatocytes derived from hESCs 150
• Cardiomyocytes derived from hESCs 150
• ESCs as source of models for drug discovery 151
• Engineered stem cells for drug delivery to the brain 152
• Use of ESCs for toxicology and drug safety studies 152
• European projects for safety testing of drugs using ESCs 153
• Pharmaceutical manipulation of stem cells 154
• Adverse effects of drugs on stem cells 156
• Future challenges for stem cell technologies 156
• Study of the molecular mechanism of cell differentiation 156
• MBD3-deficient ESC line 157
• In vivo study of human hemopoietic stem cells 157
• Stem cell biology and cancer 157
• Research into plasticity of stem cells from adults 158
• Stem cells and aging 158
• Activation of bone marrow stem cells into therapeutic cells 159
• Role of nitric oxide in stem cell mobilization and differentiation 159
• Stem cell genes 160
• Gene expression in hESCs 160
• The casanova gene in zebrafish 160
• Nanog gene 161
• Stem cell proteomics 162
• Proteomic studies of mesenchymal stem cells 162
• Proteomic profiling of neural stem cells 163
• Proteome Biology of Stem Cells Initiative 163
• Genomic alterations in cultured hESCs 163
• Hybrid embryos/cybrids for stem cell research 164
• Generation of patient-specific pluripotent stem cells 164
• Markers for characterizing hESC lines 165
• Stem cell research at academic centers 166
• International Regulome Consortium 167
• Companies involved in stem cell technologies 167
• Concluding remarks about stem cells 172
• Challenges and future prospects of stem cell research 172

4. Clinical Applications of Cell Therapy 175

• Introduction 175
• Cell therapy for hematological disorders 175
• Transplantation of autologous hematopoietic stem cells 175
• Hemophilias 175
• Ex vivo cell/gene therapy of hemophilia B 175
• Cell/gene therapy of hemophilia A 176
• Hematopoietic stem cell therapy for thrombocytopenia 177
• Stem cell transplant for sickle cell anemia 177
• Treatment of chronic acquired anemias 177
• Implantation of genetically engineered HSCs to deliver rhEpo 178
• Drugs acting on stem cells for treatment of anemia 178
• Stem cell therapy of hemoglobinopathies 178
• Stem cells for treatment of immunoglobulin-light chain amyloidosis 179
• Future prospects of cell therapy of hematological disorders 179
• Cell therapy for immunological disorders 180
• Role of dendritic cells in the immune system 180
• Modifying immune responses of DCs by vaccination with lipiodol-siRNA mixtures 180
• Stem cell therapy of chronic granulomatous disease 181
• Stem cell therapy of X-linked severe combined immunodeficiency 181
• Stem cell therapy of autoimmune disorders 181
• Treatment of Crohn' s disease with stem cells 182
• Treatment of rheumatoid arthritis with stem cells 182
• Stem cell transplants for scleroderma 182
• Role of T-Cells in immunological disorders 183
• Autologous T-cells from adult stem cells 184
• Cell therapy for graft vs host disease 184
• Cell therapy for viral infections 185
• T-cell therapy for CMV 185
• T-cell therapy for HIV infection 185
• T-cell immunity by Overlapping Peptide-pulsed Autologous Cells 186
• Anti-HIV ribozyme delivered in hematopoietic progenitor cells 186
• Dendritic-cell targeted DNA vaccine for HIV 186
• Cell therapy of lysosomal storage diseases 187
• Niemann-Pick disease 187
• Gaucher' s disease 188
• Fabry' s disease 188
• Cell therapy for diabetes mellitus 189
• Limitations of current treatment 189
• Limitations of insulin therapy for diabetes mellitus 189
• Limitations of pancreatic transplantation 190
• Islet cell transplantation 190
• Autologous pancreatic islet cell transplantation in chronic pancreatitis 190
• Clinical trials of pancreatic islet cell transplants for diabetes 191
• Drawbacks of islet cell therapy 191
• Use of an antioxidant peptide to improve islet cell transplantation 192
• Cdk-6 and cyclin D1 enhance human beta cell replication and function 192
• A device for delivery of therapeutic cells in diabetes 193
• Monitoring of islet cell transplants with MRI 193
• Concluding remarks about allogeneic islet transplantation for diabetes 193
• Encapsulation of insulin producing cells 194
• Encapsulated porcine pancreatic islet cells for pancreas 194
• Encapsulated insulinoma cells 194
• Magnetocapsule enables imaging/tracking of islet cell transplants 194
• Islet precursor cells 195
• Dedifferentiation of β cells to promote regeneration 196
• Xenotransplantation of embryonic pancreatic tissue 196
• Non-pancreatic tissues for generation of insulin-producing cells 196
• Exploiting maternal microchimerism to treat diabetes in the child 197
• Bio-artificial substitutes for pancreas 197
• Role of stem cells in the treatment of diabetes 197
• Pancreatic stem cells 197
• Embryonic stem cells for diabetes 198
• Isolation of islet progenitor cells 199
• Expansion of pancreatic progenitor cells in vitro 199
• Human neural progenitor cells converted into insulin-producing cells 200
• Insulin-producing cells derived from UCB stem cells 200
• Stem cell injection into portal vein of diabetic patients 201
• HSC transplantation to supplement immunosuppressant therapy 201
• Dendritic cell-based therapy for type 1 diabetes 201
• Gene therapy in diabetes 202
• Viral vectors for gene therapy of diabetes 202
• Genetically engineered dendritic cells 202
• Genetically altered liver cells 203
• Genetically modified stem cells 203
• Companies developing cell therapy for diabetes 203
• Concluding remarks about cell and gene therapy of diabetes 204
• Cell therapy for liver disorders 205
• Types of cells and methods of delivery for hepatic disorders 206
• Bioartificial liver 207
• Limitations of bioartificial liver 207
• Stem cells for hepatic disorders 207
• Deriving hepatocytes from commercially available hMSCs 208
• Implantation of hepatic cells derived from hMSCs of adipose tissue 209
• MSC derived molecules for reversing hepatic failure 209
• Cell-based gene therapy for liver disorders 209
• Transplantation of genetically modified fibroblasts 210
• Transplantation of genetically modified hepatocytes 210
• Intraperitoneal hepatocyte transplantation 210
• Genetically modified hematopoietic stem cells 210
• Clinical applications 211
• Future prospects of cell-based therapy of hepatic disorders 211
• Cell therapy of renal disorders 212
• Bioartificial kidney 212
• Bone marrow stem cells for renal disease 212
• Human stem cells to prevent end stage renal disease 213
• Role of stem cells in renal repair 213
• Cell-based repair for vascular access failure in renal disease 213
• Mesangial cell therapy 214
• Cell therapy for pulmonary disorders 214
• Delivery of cell therapy for pumonary disorders 214
• Intratracheal injection of cells for pulmonary hypoplasia 214
• Role of stem cells in pulmonary disorders 214
• Lung tissue regeneration from stem cells 215
• Role of stem cells in construction of the Cyberlung 215
• Respiratory epithelial cells derived from UCB stem cells 215
• Respiratory epithelial cells derived from hESCs 216
• Lung tissue engineering with adipose stromal cells 216
• Cell-based tissue-engineering of airway 217
• Pulmonary disorders that are treatable by stem cell manipulation 217
• MSCs for acute lung injury and ARDS 218
• Genetically engineered MSCs for cystic fibrosis 218
• EPCs for treatment of pulmonary arterial hypertension 218
• Cell therapy for disorders of bones and joints 219
• Repair of fractures and bone defects 219
• Adult stem cells for bone grafting 220
• Stem cells for repairing skull defects 221
• Mesenchymal stem cells for repair of bones and joints 221
• Osteocel 223
• Cell therapy for osteonecrosis 224
• Intrauterine use of MSCs for osteogenesis imperfecta 224
• Stem cell-based bone tissue engineering 224
• In vivo bone engineering as an alternative to cell transplantation 225
• Osteoarthritis and other injuries to the joints 225
• Mosaicplasty 226
• Autologous cultured chondrocytes 226
• Autologous intervertebral disc chondrocyte transplantation 227
• Cartilage repair by genetically modified fibroblasts expressing TGF-β228
• Generation of cartilage from stem cells 228
• Role of cell therapy in repair of knee cartilage injuries 229
• Role of cells in the repair of anterior cruciate ligament injury 231
• Autologous tenocyte implantation in rotator cuff injury repair 231
• Platelet injection for tennis elbow 232
• Cell therapy of rheumatoid arthritis 232
• Cell therapy for regeneration 233
• Stem cells for regeneration 233
• Umbilical cord blood for regeneration 234
• Promotion of regeneration by Wnt/beta-catenin signaling 234
• Role of stem cells in regeneration of esophageal epithelium 234
• Cell therapy for regeneration of muscle wasting 234
• MSCs for regeneration of ovaries following radiotherapy damage 235
• Wound healing: skin and soft tissue repair 235
• Cells to form skin substitutes for healing ulcers 236
• CellSpray for wound repair 236
• Role of follicular stem cells in skin and wound repair 237
• Cell therapy for burns 238
• Genetically engineered cells for wound repair 238
• Cell therapy for corneal repair 239
• Closure of incisions with laser guns and cells 240
• Repair of aging skin by injecting autologous fibroblasts 241
• Role of cells in tissue engineering and reconstructive surgery 241
• Stem cells for tissue repair 241
• Scaffolds for tissue engineering 242
• Improving vascularization of engineered tissues 242
• Enhancing vascularization by combining cell and gene therapy 243
• Choosing cells for tissue engineering 243
• ESCs vs adult SCs for tissue engineering 243
• Use of adult MSCs for tissue engineering 244
• Nanobiotechnology applied to cells for tissue engineering 244
• Strategies to improve stem cell transplantation for tissue engineering 245
• Stem cells for tissue engineering of various organs 245
• Engineering of healthy living teeth from stem cells 245
• Adipose tissue-derived stem cells for breast reconstruction 246
• Improving tissue engineering of bone by MSCs 247
• Intra-uterine repair of congenital defects using amniotic fluid MSCs 247
• Cell-based tissue engineering in genitourinary system 248
• Urinary incontinence 248
• Tissue engineering of urinary bladder 249
• Label retaining urothelial cells for bladder repair 249
• Repair of the pelvic floor with stem cells from the uterus 250
• Reconstruction of vagina from stem cells 250
• Facial skin regeneration by stem cells as an alternative to face transplant 250
• Cell therapy for rejuvenation 250
• Cell therapy for performance enhancement in sports 251
• Application of stem cells in veterinary medicine 251
• Use of stem cells to repair tendon injuries 251
• Stem cells for spinal cord injury in dogs 252

5. Cell Therapy for Cardiovascular Disorders 253

• Introduction to cardiovascular disorders 253
• Limitations of current therapies for myocardial ischemic disease 253
• Cell-mediated immune modulation for chronic heart disease 253
• Human cardiovascular progenitor cells 254
• Inducing the proliferation of cardiomyocytes 255
• Small molecules to enhance myocardial repair by stem cells 255
• Cell therapy for atherosclerotic coronary artery disease 255
• Stem cells to prevent restenosis after coronary angioplasty 256
• Transplantation of myoblasts for myocardial infarction 256
• MyoCell"! (Bioheart) 257
• Transplantation of cardiac progenitor cells for revascularization of myocardium 258
• Methods of delivery of cells to the heart 258
• Cellular cardiomyoplasty 258
• IGF-1 delivery by nanofibers to improve cell therapy for MI 259
• Non-invasive delivery of cells to the heart by MorphRguide catheter 259
• Role of cells in cardiac tissue engineering 259
• Patching myocardial infarction with fibroblast culture 259
• Cardiac repair with myoendothelial cells from skeletal muscle 259
• Myocardial tissue engineering 260
• Role of stem cells in repair of the heart 261
• Cardiac stem cells 261
• Cardiomyocytes derived from epicardium 262
• Role of stem cells in cardiac regeneration following injury 262
• Cardiomyocytes derived from ESCs 262
• Studies to identify subsets of progenitor cells suitable for cardiac repair 264
• Technologies for preparation of stem cells for cardiovascular therapy 264
• Pravastatin for expansion of endogenous progenitor and stem cells 264
• Cytokine preconditioning of human fetal liver CD133+ SCs 265
• Expansion of adult cardiac stem cells for transplantation 265
• Role of ESCs in repair of the heart 265
• ESC transplantation for tumor-free repair of the heart 266
• Transplantation of stem cells for acute myocardial infarction 267
• Autologous bone marrow-derived stem cell therapeutics 267
• Autologous bone marrow-derived mesenchymal precursor stem cells 267
• Transplantation of cord blood stem cells 267
• Transplantation of hESCs 268
• Transplantation of HSCs 268
• Transplantation of autologous angiogenic cell precursors 269
• Transplantation of adipose-derived stem cells 269
• Intracoronary infusion of bone marrow-derived cells for AMI 270
• Intracoronary infusion of mobilized peripheral blood stem cells 271
• Transplantation of endothelial cells 271
• Transplantation of cardiomyocytes differentiated from hESCs 271
• Stem cell therapy for cardiac regeneration 272
• Regeneration of the chronic myocardial infarcts by HSC therapy 272
• Human mesenchymal stem cells for cardiac regeneration 272
• In vivo tracking of MSCs transplanted in the heart 273
• MSCs for hibernating myocardium 274
• Simultaneous transplantation of MSCs and skeletal myoblasts 274
• Transplantation of genetically modified cells 274
• Transplantation of genetically modified MSCs 274
• Transplantation of cells secreting vascular endothelial growth factor 275
• Transplantation of genetically modified bone marrow stem cells 275
• Cell transplantation for congestive heart failure 275
• Myoblasts for treatment of congestive heart failure 275
• Injection of adult stem cells for congestive heart failure 276
• AngioCell gene therapy for congestive heart failure 277
• Stem cell therapy for dilated cardiac myopathy 277
• Role of cell therapy in cardiac arrhythmias 277
• Atrioventricular conduction block 278
• Genetically engineered cells as biological pacemakers 278
• Ventricular tachycardia 279
• Prevention of myoblast-induced arrhythmias by genetic engineering 279
• ESCs for correction of congenital heart defects 280
• Cardiac progenitors cells for treatment of heart disease 280
• Autologus stem cells for chronic myocardial ischemia 281
• Role of cells in cardiovascular tissue engineering 282
• Construction of blood vessels with cells 282
• Fetal cardiomyocytes seeding in tissue-engineered cardiac grafts 282
• UCB progenitor cells for engineering heart valves 282
• Stem cell therapy for peripheral vascular disease 283
• Clinical trials of cell therapy in cardiovascular disease 284
• Mechanism of the benefit of cell therapy for heart disease 286
• A critical evaluation of cell therapy for heart disease 287
• Publications of clinical trials of cell therapy for CVD 287
• Future directions for cell therapy of CVD 288

6. Cell Therapy for Cancer 289

• Introduction 289
• Cell therapy technologies for cancer 289
• Cellular immunotherapy for cancer 290
• Treatments for cancer by ex vivo mobilization of immune cells 290
• Granulocytes as anticancer agents 291
• Neutrophil granulocytes in antibody-based immunotherapy of cancer 291
• Cancer vaccines 292
• Autologous tumor cell vaccines 292
• Vaccines that simultaneously target different cancer antigens 293
• Gene modified cancer cells vaccines 293
• GVAX cancer vaccines 293
• Active immunotherapy based on antigen specific to the tumor 294
• The use of dendritic cells for cancer vaccination 294
• Basics of dendritic cell vaccines 294
• Preclinical and clinical studies with DC vaccines 294
• In vivo manipulation of dendritic cells 295
• Autologous dendritic cells loaded ex vivo with telomerase mRNA 295
• Dendritic/tumor cell fusion 295
• Genetically modified dendritic cells 296
• Limitations of DC vaccines for cancer 297
• Future developments to enhance clinical efficacy of DC vaccines 297
• Lymphocyte-based cancer therapies 298
• Adoptive immunotherapy 298
• Rescue of CD8+ T cells for use in tumor immunotherapy 299
• Expansion of antigen-specific cytotoxic T lymphocytes 300
• Genetically targeted T cells for treating B cell malignancies 300
• Tumor infiltrating lymphocytes 301
• Genetic engineering of tumor cells 301
• Hybrid cell vaccination 302
• Stem cell-based anticancer therapies 302
• Stem cell transplantation in cancer 302
• Peripheral blood stem cell transplantation 302
• Autologous stem cell transplantation 304
• Complications of stem cell transplants in cancer 305
• Long-term results of HSC transplantation 306
• Prediction of T-cell reconstitution after HSC transplantation. 306
• Role of mesenchymal stem cells in cancer 306
• Nonmyeloablative allogeneic hematopoietic stem cell transplantation 307
• Umbilical cord blood transplant for leukemia 308
• hESC-derived NK cells for treatment of cancer 308
• ESC vaccine for prevention of lung cancer 309
• Genetic modification of stem cells for cancer therapy 309
• Genetic modification of hematopoietic stem cells 309
• Use of hematopoietic stem cells to deliver suicide genes to tumors 309
• Delivery of anticancer agents by genetically engineered MSCs 310
• Mesenchymal progenitor cells for delivery of oncolytic adenoviruses 310
• Genetically modified NSCs for treatment of neuroblastoma 310
• Innovations in cell-based therapy of cancer 311
• Use of immortalized cells 311
• Cancer therapy based on natural killer cells 311
• Mesothelin as a target for cancer immunotherapy 312
• Nanomagnets for targeted cell-based cancer gene therapy 312
• Implantation of genetically modified encapsulated cells for anticancer therapy 312
• Antiangiogenesis therapy by implantation of microencapsulated cells 312
• Recombinant tumor cells secreting fusion protein 313
• NovaCaps® for pancreatic cancer 313
• A device for filtering cancer and stem cells in the blood 313
• Cancer stem cells 314
• Role of integrative nuclear signaling in stem cell development 314
• Breast cancer stem cells 314
• Role of intestinal stem cells in intestinal polyposis 315
• Role of endothelial progenitor cells in tumor angiogenesis 315
• Role of cancer stem cells in metastases 315
• Therapeutic implications of cancer stem cells 316
• Targeting cancer stem cells in leukemia 316
• Targeting stem cells in ovarian cancer 317
• Cell-based therapies for malignant brain tumors 317
• Role of cancer stem cells in resistance to radiotherapy 317
• Targeting stem cells in brain tumors 318
• Neural stem cells for drug/gene delivery to brain tumors 318
• Mesenchymal stem cells for the treatment of gliomas 319
• Bone morphogenetic protein for inhibition of glioblastoma multiforme 320
• Dendritic cell therapy for brain tumors 320
• Encapsulated cells for brain tumors 321
• Companies involved in cell-based cancer therapy 321
• American Association for Cancer Research and ESCs 323
• Future of cell-based immunotherapy for cancer 323

7. Cell Therapy for Neurological Disorders 325

• Introduction 325
• Regeneration of the nervous system by endogenous stem cells 325
• Molecular mechanism of neurogenesis 325
• Generation of neurons from astroglia 326
• In vivo cell replacement therapy by locally induced neural progenitor cells 326
• Types of cells used for treatment of neurological disorders 327
• Activated T lymphocytes 327
• Differentiation of placenta-derived multipotent cells into neurons 327
• Neural stem cells 328
• Regulation of neural stem cells in the brain 328
• Study of neural differentiation of hESCs by NeuroStem Chip 328
• Embryonic stem cell-derived neurogenesis 328
• Neural progenitor cells 330
• Distinction between NSCs and intermediate neural progenitors 331
• Development of human CNS stem cells 332
• Neural stem cells in the subventricular zone of the brain 333
• Mechanism of migration of neural stem cells to sites of CNS injury 333
• Transformation of neural stem cells into other cell types 333
• Monitoring of implanted NSCs labeled with nanoparticles 334
• Oligodendrocyte progenitor cells 334
• Proteomics of neural stem cells 334
• Use of epidermal neural crest stem cells for neurological disorders 335
• Neural stem cells as therapeutic delivery vehicles 335
• Olfactory epithelium stem cells for transplantation in the CNS 335
• Development of CNS cells from extraneural stem cells 335
• Hair-follicle stem cells for neural repair 336
• Stem cells from human umbilical cord blood for CNS disorders 337
• Immortalized cells for CNS disorders 337
• Fetal tissue transplants 338
• Choroid plexus cells 338
• Laboratory mice with human brain cells 339
• Expansion of adult human neural progenitors 339
• Neurospheres 339
• Ideal cells for transplantation into the nervous system 340
• Cell therapy techniques for neurological applications 340
• Stem cells preparations for CNS disorders 340
• Neuronal differentiation of stem cells 341
• hESCs for CNS repair 342
• Enhancement of growth of stem cells in the brain by drugs 342
• Carbon nanotubes to aid stem cell therapy of neurological disorders 343
• Use of neural stem cells to construct the blood brain barrier 343
• Tracking of stem cells in the CNS by nanoparticles and MRI 344
• Methods of delivery of cells to the CNS 344
• Encapsulated cells 345
• CNS neotissue implant 345
• Intrathecal delivery of stem cells 346
• CNS delivery of cells by catheters 346
• Intravascular administration 346
• Cells used for gene therapy of neurological disorders 347
• Fibroblasts 347
• Stem cells 348
• Neuronal cells 348
• Immortalized neural progenitor cells 348
• Astrocytes 349
• Cerebral endothelial cells 349
• Human retinal pigmented epithelial cells 350
• Neurological disorders amenable to cell therapy 350
• Neuroprotection by cell therapy 350
• Cells secreting neuroprotective substances 351
• Stem cells for neuroprotection 351
• Neuroprotection by intravenous administration of HSCs 351
• Human UCB-derived stem cells for the aging brain 351
• Neurodegenerative disorders 352
• Role of stem cells in neurodegenerative disorders 352
• MSCs for therapy of neurodegenerative disorders 352
• Role of NSCs in disorders associated with aging brain 354
• NSCs for improving memory 354
• Parkinson' s disease 354
• Origin and fate of dopamine neurons 356
• Human dopaminergic neurons for PD 356
• Graft survival-enhancing drugs 357
• Xenografting porcine fetal neurons 357
• Encapsulated cells for PD 357
• Stem cells for PD 358
• Stem cells for production of glial derived neurotrophic factor 360
• Potential of regeneration of endogenous stem cells in PD 360
• Human retinal pigment epithelium cells for PD 361
• Coaxing hESCs to produce dopamine 361
• Tumorigenic potential of transplantated dopaminergic hESCs 362
• Delivery of cells for PD 362
• MSCs for multiple system atrophy 362
• Cell therapy for Huntington' s disease 362
• Fetal striatal cell transplantation 363
• Transplantation of encapsulated porcine choroids plexus cells 363
• Cell therapy for Alzheimer' s disease 363
• Neural stem cell implantation for Alzheimer' s disease 364
• Implantation of genetically engineered cells producing NGF 364
• Cell therapy for amyotrophic lateral sclerosis 365
• Cell nuclear replacement technique for study of ALS 365
• Use of stem cells for ALS 365
• Transplantation of glial restricted precursors in ALS 366
• Stem cell-based drug discovery for ALS 367
• Cell therapy for lysosomal storage disorders 367
• Cell therapy for Batten disease 367
• Genetically modified HSCs for metachromatic leukodystrophy 368
• Cell therapy for demyelinating disorders 368
• Hematopoietic stem cell transplantation for multiple sclerosis 369
• Embryonic stem cells for remyelination 369
• Neural precursor cells for neuroprotection in multiple sclerosis 370
• Stem cells for chronic inflammatory demyelinating polyneuropathy 370
• Cell therapy of stroke 370
• Transplantation of encapsulated porcine choroids plexus 371
• Transplantation of fetal porcine cells 371
• Adult stem cell therapy in stroke 372
• Implantation of genetically programmed ESCs 372
• Intravenous infusion of marrow stromal cells 373
• Intravenous infusion of umbilical cord blood stem cells 373
• Intracerebral administration of human adipose tissue stromal cells 374
• Intracerebral administration of multipotent adult progenitor cells 374
• Neural stem cell therapy for stroke 374
• Future of cell therapy for stroke 375
• Cell therapy of traumatic brain injury 376
• Cell/gene therapy for TBI 376
• Clinical trials of autologous HSC therapy for TBI 377
• Limitations of stem cell therapy for acute TBI 377
• Improving the microenvironments of transplanted cells in TBI 378
• Cell therapy for spinal cord injury 378
• Fetal neural grafts for SCI 378
• Olfactory-ensheathing cells for SCI 379
• Oligodendrocyte precursor cells for treatment of SCI 379
• Schwann cell transplants for SCI 379
• Transplantation of glial cells for SCI 380
• Stem cells for SCI 380
• Bone marrow stem cells for SCI 380
• Embryonic stem cells for SCI 380
• Transplantation of MSCs for SCI 381
• Transplantation of NSCs for SCI 381
• Transdifferentiation of BM stem cells into cholinergic neurons for SCI 382
• Spinal stem cells for treatment of ischemic injury of spinal cord 382
• Combined approaches for regeneration in SCI 383
• Combined cell/gene therapy for SCI 383
• Delivery of cells in SCI 383
• Intrathecal injection of cells labeled with magnetic nanoparticles 384
• Intravenous injection of stem cells for spinal cord repair 384
• Clinical applications of stem cells for SCI 384
• Autologous bone marrow cell transplantation for SCI 384
• Cell therapy of syringomyelia 385
• Umbilical cord blood stem cells for neurogenetic disorders 385
• UCB stem cells for Krabbe' s disease 385
• UCB stem cells for Hurler' s syndrome 385
• UCB stem cells for Sanfilippo syndrome type B 386
• Combination of cell and gene therapy for Krabbe' s disease 386
• Cell therapy of epilepsy 387
• Cell therapy of posttraumatic epilepsy 387
• Cell therapy for temporal lobe epilepsy 387
• Cell therapy for pharmacoresistant epilepsies 388
• Cell therapy for developmental neurological disorders 388
• Cell therapy for cerebral palsy 388
• Cell therapy for muscular dystrophy 389
• Cell transplant for Duchenne muscular dystrophy 389
• Myoblast-based gene transfer 390
• Transplantation of myoblasts lacking the MyoD gene 390
• HSCs for DMD 391
• Improvement of DMD therapy by using muscle-derived stem cells 391
• Combination of cell and pharmacotherapy for DMD 392
• Cell therapy for Autism 392
• Management of chronic intractable pain by cell therapy 393
• Implantation of chromaffin cells 393
• Role of stem cells in management of pain 394
• Implantation of astrocytes secreting enkephalin 394
• Cells for delivery of antinociceptive molecules 394
• Implantation of genetically engineered cells 395
• Cell therapy for low back pain 395
• Cell therapy for retinal degenerative disorders 395
• Genetically engineered retinal pigmented epithelial cell lines 396
• Delivery of CNTF by encapsulated cell intraocular implants 397
• Stem cell transplantation in the retina 397
• Isolation of RPE cells from hESCs using transcriptomics 398
• ESCs for retinal degenerative disorders 398
• Neuroprotective effect of neural progenitor cell transplantation 398
• Human retinal stem cells 398
• Combining cell and gene therapies for retinal disorders 399
• Stem cell therapy for hearing loss 399
• Cell thery for peripheral nerve lesions 400
• Cell transplants for peripheral nerve injuries 400
• Treatment of diabetic neuropathy with endothelial progenitor cells 400
• Clinical trials of cell therapy in neurological disorders 400
• Future prospects for cell therapy of CNS disorders 401

8. Ethical, Regulatory, and Safety Aspects of Cell Therapy 403

• Introduction 403
• Safety issues of cell therapy 403
• Immune-mediated reactions to transpanted stem cells 403
• Human virus infections associated with stem cell transplantation 404
• Herpes simplex virus type 1 404
• Cytomegalovirus 404
• Opportunistic infections among hematopoietic stem cell transplant recipients 404
• Carcinogenic potential of stem cells and its prevention 405
• FDA safety regulations for cell and tissue products 405
• FDA Guidance on license applications for umbilical cord blood products 406
• Political and ethical aspects of hESC research in the US 406
• Ethical issues concerning fetal tissues 406
• Morality and hESC research 407
• Opponents of hESC research in the US 407
• Ban on cloning and impact on hESC research 408
• Political aspects of human hESC research in the US 408
• Use of hESCs in NIH-supported research 409
• Public opinion in the US about hESC research 410
• Scientists' view of stem cell research in the US 411
• New developments in stem cell research in the US 413
• Human stem cell cloning in the US 414
• Stem cell guidelines of various US institutions 414
• Ethics of transplanting human NSCs into the brains of nonhuman primates 415
• Stem cell lines available worldwide 416
• Stem cell policies around the world 417
• Countries with no defined policies on hESC research 417
• Australia 418
• Canada 418
• China 419
• Denmark 420
• France 420
• Germany 420
• India 422
• Ireland 423
• Israel 423
• Italy 423
• Japan 424
• The Netherlands 424
• Saudi Arabia 425
• Singapore 425
• South Africa 425
• South Korea 426
• Spain 426
• Sweden 426
• Switzerland 427
• United Kingdom 427
• ESC bank 428
• European Union 429
• EU guidelines for stem cell research 429
• EMBO' s recommendations for stem cell research 430
• United Nations, cloning and nuclear transfer 431
• The Embryo Project for information on ESC research 432
• Concluding remarks about ethics of ESC research 432
• Ethical issues concerning umbilical cord blood 432
• Regulatory issues 433
• Regulation of cord blood banks in the US 433
• Regulatory issues for biotechnology-derived drugs 433
• Regulation of cell selection devices for production of PBSCs at point of care 434
• FDA rules for human cells and tissues 434
• FDA regulation of fetal cellular or tissue products 435
• FDA and clinical trials using hESCs 436
• Cell and gene therapy INDs placed on hold by the FDA 436
• NIH regulation of fetal cellular or tissue products 437
• Regulatory issues for genetically engineered cell transplants 437
• FDA guidelines for human tissue transplantation 437
• Xenotransplantation 438
• Clinical Protocol Review and Oversight 438
• Informed consent and patient education 438
• Xenotransplantation product sources 438
• FDA guidelines for xenografts 439
• Regulations relevant to cell therapy in the European Union 441
• Regulations about use of stem cells 441
• EMEA regulation of cell/gene therapy 441
• Guidelines for cell therapy in the UK 442
• Stem cell patents 443
• Stem cell patents in the United States 443
• Current status of Thomson patents at WARF 444
• Stem cell patents in the European Union 444

9. Markets and Future Prospects for Cell Therapy 447

• Introduction 447
• Methods for estimation of cell therapy markets 447
• Potential markets for cell therapy 448
• Markets according to technologies 448
• Stem cell transplant 448
• Blood transfusion market 448
• Cord blood collection and storage 449
• Cell therapy and related technologies 449
• Cell therapy markets according to therapeutic area 449
• Bone and joint disorders 450
• Cancer 450
• Cardiovascular disorders 450
• Diabetes mellitus 451
• Liver disorders 451
• Neurological disorders 452
• Retinal degenerative diseases market 452
• Skin and wound care 452
• Urinary incontinence 453
• Reconstruction of teeth by stem cell implants 453
• Market size according to geographical areas 453
• Unmet market needs in cell therapy 454
• Future prospects of cell therapy 455
• Role of stem cells in regenerative medicine 455
• Role of cells in markets for artificial organs 456
• Clinical trials in cell therapy 456
• Embryonic stem cell research around the world 456
• Consortia for ESC research in Europe 457
• EuroStemCell 457
• FunGenES 458
• ESTOOLS 458
• UK National Stem Cell Network 459
• Ethical concerns about commercialization of embryonic stem cells 460
• Education of the physicians 460
• Public education 460
• NIH support of stem cell research 460
• Funding of stem cell research from non-federal sources 461
• Prospects of venture capital support for stem cell companies 462
• Cell therapy in the developing countries 463
• Guidelines for stem cell therapies 464
• Business strategies 464
• Formation of networks 465
• Future market potential of adult vs embryonic stem cells 465

10. References 467

Tables

• Table 1 1: Landmarks in the history of cell therapy 25
• Table 1 2: Examples of cells involved in various diseases 30
• Table 2 1: Types of human cells used in cell therapy 33
• Table 2 2: A selection of companies providing cell culture media 37
• Table 2 3: A sampling of companies supplying cell sorters 40
• Table 2 4: Companies involved in cell-based drug discovery 45
• Table 2 5: Methods of delivery of cells for therapeutic purposes 47
• Table 2 6: Therapeutic applications of encapsulated cells 51
• Table 2 7: Companies working on encapsulated cell technology 54
• Table 2 8: Methods for tracking cells in vivo 59
• Table 3 1: Companies involved in cord blood banking as a source of stem cells 93
• Table 3 2: Sources of adult human stem cells 96
• Table 3 3: Enhancing engraftment, mobilization and expansion of stem cells 118
• Table 3 4: Applications of stem cells 135
• Table 3 5: Growth factors with positive effects on stem cells and applications 154
• Table 3 6: Examples of drugs that induce granulocytopenia at stem cell level 156
• Table 3 7: Academic institutes involved in stem cell research 166
• Table 3 8: Companies involved in stem cell technologies 167
• Table 4 1: Therapeutic applications of regulatory T cells (T-regs) 183
• Table 4 2: Various tissue/cell therapy approaches to the treatment of type 1 diabetes 189
• Table 4 3: Companies involved in cell therapy for insulin-dependent diabetes 204
• Table 4 4: Major pulmonary disorders potentially treatable by stem cell manipulation 217
• Table 4 5: Cell-based repair of knee cartilage damage 230
• Table 5 1: Clinical trials of cell therapy in cardiovascular disease 284
• Table 6 1: Cell therapy technologies used for cancer 289
• Table 6 2: Companies involved in developing cell-based therapies for cancer 322
• Table 7 1: Experimental use of immortalized cells for CNS disorders 337
• Table 7 2: Methods for delivering cell therapies in CNS disorders 344
• Table 7 3: Neurological disorders amenable to cell therapy 350
• Table 7 4: Types of cell used for investigative treatment of Parkinson' s disease 355
• Table 7 5: Status of cell therapies for Parkinson' s disease 355
• Table 7 6: Clinical trials with cell-based therapies in neurological disorders 400
• Table 8 1: Possible adverse reactions and safety issues of cell therapy 403
• Table 8 2: Numbers of stem cell lines around the world 416
• Table 8 3: Stem cell policies around the world 417
• Table 9 1: Market size according to cell therapy and related technologies 2008-2018 448
• Table 9 2: Market size according to therapeutic areas for cell therapy 2008-2018 449
• Table 9 3: Cell therapy markets for cardiovascular disorders 2008-2018 450
• Table 9 4: Values of cell therapies for neurological disorders 2008-2018 452
• Table 9 5: Total cell therapy market according to geographical areas 2008-2018 453
• Table 9 6: Cord blood market according to geographical areas 2008-2018 454
• Table 9 7: Stem cells transplant market according to geographical areas 2008-2018 454

Figures

• Figure 1 1: Interrelationships of cell therapy to other technologies 27
• Figure 1 2: Interrelationships of gene, cell and protein therapies 29
• Figure 3 1: A simplified biological scheme of embryonic stem Cells 66
• Figure 3 2: Steps of iPS cell production 105
• Figure 3 3: Flow chart of development of stem cells with potential bottlenecks 173
• Figure 5 1: hESC-derived cardiomyocytes from laboratory to bedside 263
• Figure 6 1: A scheme of generation and administration of tumor antigen-pulsed dendritic cells 297
• Figure 6 2: Stem cell transplantation techniques 303
• Figure 7 1: Stem cells that can give rise to neurons 331
• Figure 7 2: Approaches to stem cell therapy in stroke 372
• Figure 9 1: Unmet needs in cell therapy 455