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Cell Therapy - Technologies, Markets and Companies

Notes

Cell therapy has applications in a large number of disorders. This report will provide an in-depth analysis of the cell therapy market as well as the technology used to help treat a variety of disorders.

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 2013, and projected to 2023.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 294 of these are profiled in part II of the report along with tabulation of 285 alliances. Of these companies, 160 are involved in stem cells. Profiles of 72 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 61 Tables and 16 Figures. The bibliography contains 1,200 selected references, which are cited in the text.

Table of Contents

Part I

0. Executive Summary 25

1. Introduction to Cell Therapy 29

  • Introduction 29
  • Historical landmarks of cell therapy 29
  • Interrelationship of cell therapy technologies 31
  • Cells and organ transplantation 32
  • Cells and protein/gene therapy 32
  • Cell therapy and regenerative medicine 33
  • Cells therapy and tissue engineering 34
  • Therapy based on cells involved in disease 34
  • Advantages of therapeutic use of cells 35
  • Cell-based drug delivery 35
  • Cells as vehicles for gene delivery 35
  • Red blood cells as vehicles for drug delivery 36
  • Advantages of cell-based drug delivery 37
  • Limitations of cell-based drug delivery 37

2. Cell Therapy Technologies 39

  • Introduction 39
  • Cell types used for therapy 39
  • Sources of cells 39
  • Xenografts 40
  • Cell lines 40
  • Immortalized cells 40
  • Blood component therapy 40
  • Therapeutic apheresis 40
  • Leukoreduction 41
  • Platelet therapy 41
  • Basic technologies for cell therapy 42
  • Cell culture 42
  • Automated cell culture devices 42
  • Cell culture for adoptive cell therapy 43
  • Observation of stem cell growth and viability 43
  • OpTmizer™ CTS™ T cell expansion tissue culture medium 43
  • Companies involved in cell culture 43
  • Cell sorting 45
  • Flow cytometry 45
  • Applications of flow cytometry 46
  • A dielectrophoretic system for cell separation 46
  • Adult stem cell sorting by identification of surface markers 46
  • ALDESORTER system for isolation of stem cells 47
  • Dynabead technology for cell sorting 47
  • Elutra® Cell Separation System 47
  • Magnetophoretic array-based cell sorting for further studies 48
  • Molecular beacons for specific detection and isolation of stem cells 48
  • Multitarget magnetic activated cell sorter 48
  • Nanocytometry 49
  • Scepter™ cytometer 49
  • Companies supplying cell sorters 49
  • Cell analysis 50
  • Cell analyzers 50
  • In vivo cell imaging 51
  • Measuring cell density 51
  • Single-cell gene expression analysis 51
  • Fluorescent in situ RNA sequencing 53
  • Preservation of cells 53
  • Innovations in cryopreservation 53
  • Packaging of cells 54
  • Selective expansion of T cells for immunotherapy 55
  • Cloning and cell therapy 55
  • Techniques for cell manipulation 56
  • Altering function of adult human cells 56
  • Cell-based drug discovery 57
  • Advantages and limitations of cell-based assays for drug discovery 57
  • Advantages and limitations of cell-based toxicity screening 57
  • Quality control of cells for drug discovery 58
  • Companies involved in cell-based drug discovery 58
  • Drug delivery systems for cell therapy 60
  • Intravenous delivery of stem cells 60
  • Intraarterial delivery of stem cells 60
  • Pharmacologically active microcarriers 60
  • Targeted delivery of engineered cells to specific tissues via circulation 61
  • Devices for delivery of cell therapy 61
  • Artificial cells 62
  • Applications of artificial cells 62
  • Cell encapsulation 63
  • Cell-in-a-Box® 63
  • Diffusion capsule for cells 64
  • Encapsulated cell biodelivery 64
  • Therapeutic applications of encapsulated cells 64
  • Nitric oxide delivery by encapsulated cells 66
  • Implantation of microencapulated genetically modified cells 66
  • Ferrofluid microcapsules for tracking with MRI 67
  • Companies involved in encapsulated cell technology 67
  • Electroporation 68
  • Gene therapy 68
  • Cell-mediated gene therapy 69
  • Fibroblasts 69
  • Chondrocyte 70
  • Skeletal muscle cells 70
  • Vascular smooth muscle cells 70
  • Keratinocytes 71
  • Hepatocytes 71
  • Lymphocytes 71
  • Mammalian artificial chromosomes 72
  • In vivo tracking of cells 72
  • Molecular imaging for tracking cells 72
  • MRI technologies for tracking cells 73
  • Superparamagnetic iron oxide nanoparticles as MRI contrast agents 73
  • Visualization of gene expression in vivo by MRI 74
  • Optogenetic monitoring of cell therapies 74
  • Role of nanobiotechnology in development of cell therapy 75
  • Cell transplantation for development of organs 75
  • Cells transplantation and tolerance 76
  • Strategies to improve tolerance of transplanted cells 76
  • Encapsulation to prevent immune rejection 76
  • Prevention of rejection of xenotransplants 76
  • Expansion of allospecific regulatory T cells 77
  • Removal and replacement of pathogenic cells of the body 77
  • Therapeutic leukocytapheresis 78

3. Stem Cells 79

  • Introduction 79
  • Biology of stem cells 79
  • Embryonic stem cells 80
  • Growth and differentiation of ESCs 80
  • Mechanisms of differentiation of ESCs 81
  • Chemical regulation of stem cell differentiation 81
  • In vitro differentiation of hESCs 81
  • SIRT1 regulation during stem cell differentiation 82
  • Regulation of stem cell self-renewal and differentiation 82
  • hESCs for reprogramming human somatic nuclei 82
  • Stem cells differentiation in the pituitary gland 83
  • Influence of microenvironment on ESCs 83
  • Role of genes in differentiation of ESCs 83
  • Global transcription in pluripotent ESCs 83
  • Role of p53 tumor suppressor gene in stem cell differentiation 84
  • Role of Pax3 gene in stem cell differentiation 84
  • Signaling pathways and ESC genes 84
  • Epigenetics of hESCs 85
  • Chromatin as gene regulator for ESC development 86
  • Mechanism of regulation of stem cells for regeneration of body tissues 86
  • Role of microenvironments in the regulation of stem cells 86
  • Regulation and regeneration of intestinal stem cells 87
  • Parthenogenesis and human stem cells 87
  • Uniparental ESCs 88
  • Bone marrow stem cells 89
  • Hematopoietic stem cells 89
  • Role of HSCs in the immune system 90
  • Derivation of HSCs from ESCs 91
  • Mesenchymal stem cells 91
  • Multipotent adult progenitor cells 93
  • Side population (SP) stem cells 93
  • Differentiation of adult stem cells 94
  • Growth and differentiation of HSCs 95
  • HSCs and aging 95
  • Mathematical modeling of differentiation of HSCs 95
  • Role of prions in self renewal of HSCs 96
  • Signaling pathways in the growth and differentiation of HSCs 96
  • Sources of stem cells 97
  • Sources of of human embryonic stem cells 97
  • Nuclear transfer to obtain hESCs 97
  • Direct derivation of hESCs from embryos without nuclear transfer 98
  • Alternative methods of obtaining hESCs 98
  • Establishing hESC lines without destruction of embryo 99
  • Altered nuclear transfer 100
  • Advantages and disadvantages of ESCs for transplantation 100
  • Use of ESC cultures as an alternative source of tissue for transplantation 100
  • Spermatogonial stem cells 101
  • Very small embryonic-like stem cells 102
  • Amniotic fluid as a source of stem cells 102
  • Amniotic fluid stem cells for tissue repair and regeneration 103
  • Generation of iPS cells from AF cells 103
  • Placenta as source of stem cells 104
  • Amnion-derived multipotent progenitor cells 104
  • Placenta as a source of HSCs 104
  • Umbilical cord as a source of MSCs 105
  • Umbilical cord blood as source of neonatal stem cells 105
  • Cryopreservation of UCB stem cells 106
  • Epigenetic programming for expansion of UCB cells 106
  • UCB as source of MSCs 107
  • Applications of UCB 107
  • Advantages of UCB 107
  • Limitations of the use of UCB and measures to address them 108
  • Licensing and patent disputes involving UCB 109
  • Infections following UCB transplants 109
  • Unanswered questions about UCB transplantation 110
  • Companies involved in UCB banking 110
  • UCB banking in the UK 111
  • US national UCB banking system 112
  • Future prospects of UCB as a source of stem cells 113
  • Techniques of nuclear reprogramming for stem cells 113
  • Induced pluripotent stem cells derived from human somatic cells 114
  • Characteristics of iPSCs 114
  • DNA methylation patterns of iPS cells 115
  • Techniques for obtaining iPSCs 115
  • iPSCs derived from skin 115
  • iPSCs derived through somatic cell nuclear transfer (SCNT) 116
  • iPSCs derived from oocytes 116
  • iPSCs derived from adult stem cells using SCNT 116
  • iPSCs derived from blood 116
  • Use of retroviral vectors for generation of iPSCs 117
  • Use of non-integrating viral vectors for generation of iPSCs 117
  • Generation of other cells from iPSCs 118
  • Generation of HSCs from iPSCs 118
  • Generation of MSCs from iPSCs 118
  • Generation of RBCs from iPSCs 119
  • Banks providing patient-specific iPSC lines 119
  • Companies providing iPSCs 119
  • Generation of clinically relevant iPSCs 120
  • iPSCs and disease modeling 121
  • iPSCs for patient-specific regenerative medicine 121
  • Concluding remarks about clinical potential of iPSCs 121
  • Induced conditional self-renewing progenitor cells 122
  • Epiblast stem cells 123
  • Comparison of development of human and mouse ESCs 123
  • Conversion of hESCs to mouse ESC-like naïve states 123
  • Sources of adult human stem cells 124
  • Adipose tissue as a source of stem cells 124
  • Intravenous infusion of adipose tissue derived MSCs 124
  • iPSCs derived from adult human adipose stem cells 125
  • Regulation of adipose stem cells differentiation 125
  • Transforming adult adipose stem cells into other cells 125
  • Multipotent stem-like cells derived from vascular endothelial cells 125
  • Skin as a source of stem cells 126
  • Controlling the maturation of embryonic skin stem cells 126
  • Epidermal neural crest stem cells 126
  • Follicle stem cells 127
  • Mesenchymal stem cells in skin 127
  • Regulation of stem cells in hair follicles 128
  • Skin-derived precursor cells 128
  • Regulation of epidermal stem cells by circadian rhythms 128
  • Stem cells in teeth 128
  • Peripheral blood stem cells 129
  • Spleen as a source of adult stem cells 130
  • Search for master stem cells 130
  • Vascular cell platform to self-renew adult HSC 130
  • Adult stem cells vs embryonic stem cells 131
  • Biological differences between adult and embryonic stem cells 131
  • Neural crest stem cells from adult hair follicles 131
  • Transdifferentiation potential of adult stem cells 132
  • Attempts at stimulus-triggered acquisition of pluripotentcy 133
  • Limitations of adult stem cells 133
  • Comparison of human stem cells according to derivation 134
  • VENT cells 134
  • ESC banking 134
  • Stem cell technologies 135
  • Analysis of stem cell growth and differentiation 135
  • Activation of bone marrow stem cells into therapeutic cells 135
  • Role of nitric oxide in stem cell mobilization and differentiation 135
  • Role of natriuretic peptide receptor-C in self-renewal of murine ESCs 136
  • Stem cell biomarkers 136
  • Endoglin as a functional biomarker of HSCs 136
  • STEMPRO® EZChek™ for analysis of biomarkers of hESCs 137
  • SSEA-4 as biomarker of MSCs 137
  • p75NTR as a biomarker to isolate adipose tissue-derived stem cells 137
  • Neural stem cell biomarker 137
  • Protein expression profile as biomarker of stem cells 138
  • Real-time PCR for quantification of protein biomarkers 138
  • Study of stem cell pathways 138
  • Stem cell genomics 139
  • Gene expression in hESCs 139
  • Genomic alterations in cultured hESCs 139
  • Study of transcriptional regulation of stem cell genes 140
  • Casanova gene in zebrafish 140
  • Nanog gene 140
  • Gene inactivation to study hESCs 142
  • RNAi to study gene inactivation in hESCs 142
  • Study of ESC development by inducible RNAi 142
  • Targeting Induced Local Lesions in Genomes 143
  • Homologous recombination of ESCs 143
  • Gene modification in genomes of hESCs and hiPSCs using zinc-finger nuclease 143
  • miRNA and stem cells 144
  • Role of miRNAs in gene regulation during stem cell differentiation 144
  • Influence of miRNA on stem cell formation and maintenance 145
  • Transcriptional regulators of ESCs control miRNA gene expression 145
  • Stem cells and cloning 145
  • Cell nuclear replacement and cloning 145
  • Nuclear transfer and ESCs 146
  • Cloning from differentiated cells 147
  • Cloning mice from adult stem cells 147
  • Creating interspecies stem cells 148
  • Cloned cells for transplantation medicine 148
  • Claims of cloning of hESCs 149
  • hESCs derived by SCNT 150
  • Cytogenetics of embryonic stem cells 151
  • Stem cell proteomics 151
  • Comparative proteomic analysis of somatic cells, iPSCs and ESCs 152
  • hESC phosphoproteome 152
  • Proteomic studies of mesenchymal stem cells 153
  • Proteomic profiling of neural stem cells 153
  • Proteome Biology of Stem Cells Initiative 153
  • Technologies for mobilization, expansion, and engraftment of stem cells 154
  • Chemoattraction of neuronal stem cells through GABA receptor 154
  • Enhancement of HSC engraftment by calcium-sensing receptor 155
  • Ex vivo expansion of human HSCs in culture 155
  • Ex vivo expansion of MSCs 156
  • Ex vivo expansion of UCB cells for transplantation 156
  • Expansion of adult stem cells by activation of Oct4 156
  • Expansion of transduced HSCs in vivo 156
  • Expansion of stem cells in vivo by Notch receptor ligands 157
  • In vivo adipogenesis induced by adipose tissue-derived stem cells 157
  • Selective mobilization of progenitor cells from bone marrow 157
  • Selective Amplification 158
  • Synthetic substrates for ESC growth and expansion 158
  • Technologies for inducing differentiation of stem cells 158
  • Enhancement of stem cell differentiation by Homspera 158
  • Generation of RBCs from HSCs 159
  • Generation of multiple types of WBCs from hESCs and iPSCs 159
  • Growth factor-induced differentiation of MAPCs 160
  • Lineage selection to induce differentiation of hESCs 160
  • Mechanical strain to induce MSC differentiation 160
  • Neurotrophin-mediated survival and differentiation of hESCs 160
  • Synthetic biology and stem cells 161
  • Use of RNAi to expand the plasticity of autologous adult stem cells 161
  • Use of carbohydrate molecules to induce differentiation of stem cells 162
  • Limitations of the currently available stem cell lines in the US 162
  • Stem cell separation 162
  • Stem cell culture 163
  • Culture of hMSCs 164
  • Elimination of contaminating material in stem cell culture 164
  • Long-term maintenance of MSC multipotency in culture 165
  • Nanofiber scaffolds for stem cell culture 166
  • Conversion of stem cells to functioning adipocytes 166
  • Mass production of ESCs 166
  • Promoting survival of dissociated hESCs 167
  • Analysis and characterization of stem cells 167
  • Havesting and identification of EPCs 168
  • Labeling of stem cells 168
  • Labeling, imaging and tracking of stem cells in vivo 169
  • Perfluorocarbon nanoparticles to track therapeutic cells in vivo 169
  • PET imaging for tracking of stem cells 169
  • Project for imaging in stem cell therapy research 169
  • Quantum dots for labeling and imaging of stem cells 170
  • Radiolabeling of MSCs for in vivo tracking 170
  • Superparamagnetic iron oxide nanoparticles for tracking MSCs 170
  • Tracking of transplanted muscle stem cells 171
  • Applications of stem cells 171
  • Commercial development and applications of adult stem cells 172
  • Preparation of cells for therapeutic administration to patients 172
  • Retrodifferentiation of stem cells 172
  • MultiStem 172
  • Controlling the maintenance process of hematopoietic stem cells 173
  • Self renewal and proliferation of HSCs 173
  • Aging and rejuvenation of HSCs 173
  • Aging and MSCs 174
  • iPSC-based modeling of late-onset age-related diseases 174
  • Peripheral blood stem cell transplantation 174
  • Role of stem cells in regeneration 175
  • Promotion of regeneration by Wnt/beta-catenin signaling 175
  • Stem cell activation for regeneration by using glucocortoids 175
  • Stem cells and human reproduction 176
  • Expansion of spermatogonial stem cells 176
  • Conversion of ESCs into spermatogonial stem cells 176
  • Conversion of stem cells to oocytes 177
  • ESCs for treatment of infertility in women 177
  • Cloning human embryos from oocytes matured in the laboratory 178
  • In utero stem cell transplantation 178
  • Innovations in delivery of stem cells 179
  • Polymeric capsules for stem cell delivery 179
  • Immunological aspects of hESC transplantation 180
  • Immunosuppression to prevent rejection of hESC transplants 180
  • Histocompatibility of hESCs 180
  • Strategies for promoting immune tolerance of hESCs 181
  • Stem cells for organ vascularization 181
  • Activation of EphB4 to enhance angiogenesis by EPCs 182
  • Advantages and limitations of clinical applications of iPSCs 182
  • Advantages and limitations of clinical applications of MSCs 183
  • Biofusion by genetically engineering stem cells 183
  • Stem cell gene therapy 183
  • Combination of gene therapy with nuclear transfer 184
  • Gene delivery to stem cells by artificial chromosome expression 184
  • Genetic manipulation of ESCs 184
  • Genetic engineering of human stem cells for enhancing angiogenesis 185
  • HSCs for gene therapy 185
  • iPSCs for targeted gene correction of α1-antitrypsin deficiency 186
  • Helper-dependent adenoviral vectors for gene transfer in ESCs 186
  • Lentiviral vectors for in vivo gene transfer to stem cells 186
  • Linker based sperm-mediated gene transfer technology 187
  • Mesenchymal stem cells for gene therapy 187
  • Microporation for transfection of MSCs 187
  • Regulation of gene expression for SC-based gene therapy 187
  • Stem cells and in utero gene therapy 188
  • Therapeutic applications for hematopoietic stem cell gene transfer 188
  • Targeted genome editing for human repopulating HSCs 188
  • The future of hematopoietic stem cell gene therapy 189
  • Stem cell pharmaceutics 189
  • Pharmaceutical manipulation of stem cells 189
  • Antisense approach for preservation and expansion of stem cells 190
  • Expansion of HSCs in culture by inhibiting aldehyde dehydrogenase 191
  • Manipulation of stem cells with growth factors 191
  • Mobilization of stem cells by cytokines/chemokines 193
  • Mobilization of adult human HSCs by use of inhibitors 194
  • Mobilization of stem cells by HYC750 195
  • Mobilization of stem cells by hyperbaric oxygen 195
  • Mobilization by adenoviral vectors expressing angiogenic factors 196
  • Stem cell mobilization by acetylcholine receptor agonists 196
  • Use of parathyroid hormone to increase HSC mobilization 196
  • Use of small molecule compounds for expansion of HSCs 196
  • Role of stem cells in therapeutic effects of drugs 197
  • Stem cells for drug discovery 197
  • Target identification 197
  • High-throughput screening 198
  • Cardiomyocytes derived from hESCs 198
  • ESCs as source of models for drug discovery 199
  • hESC-derived hepatocytes for drug discovery 199
  • Advantages and limitations of use of stem cells for drug discovery 200
  • Stem cells for drug delivery 201
  • Toxicology and drug safety studies using ESCs versus other cells 201
  • Future challenges for stem cell technologies 203
  • Generation of patient-specific pluripotent stem cells 203
  • Hybrid embryos/cybrids for stem cell research 204
  • In vivo study of human hemopoietic stem cells 205
  • Inhibition of stem cell-derived teratoma formation by small molecules 205
  • Markers for characterizing hESC lines 205
  • MBD3-deficient ESC line 206
  • Research into plasticity of stem cells from adults 206
  • Stem cell biology and cancer 206
  • Stem cells and aging 207
  • Stem cells in space 208
  • Study of the molecular mechanism of cell differentiation 209
  • Switch of stem-cell function from activators to repressors 209
  • Stem cell research at academic centers 210
  • International Regulome Consortium 211
  • Companies involved in stem cell technologies 211
  • Concluding remarks about stem cells 216
  • Challenges and future prospects of stem cell research 216

4. Clinical Applications of Cell Therapy 219

  • Introduction 219
  • Cell therapy for hematological disorders 219
  • Transplantation of autologous hematopoietic stem cells 219
  • Hemophilias 219
  • Ex vivo cell/gene therapy of hemophilia B 220
  • Cell/gene therapy of hemophilia A 220
  • Hematopoietic stem cell therapy for thrombocytopenia 221
  • Stem cell transplant for sickle cell anemia 221
  • Treatment of chronic acquired anemias 222
  • Implantation of genetically engineered HSCs to deliver rhEpo 222
  • Drugs acting on stem cells for treatment of anemia 222
  • Stem cell therapy of hemoglobinopathies 223
  • Stem cells for treatment of immunoglobulin-light chain amyloidosis 223
  • Future prospects of cell therapy of hematological disorders 223
  • Cell therapy for immunological disorders 224
  • Role of dendritic cells in the immune system 224
  • Modifying immune responses of DCs by vaccination with lipiodol-siRNA mixtures 224
  • Potential of MSCs as therapy for immune-mediated diseases 225
  • Stem cell therapy of chronic granulomatous disease 225
  • Stem cell therapy of X-linked severe combined immunodeficiency 226
  • Stem cell therapy of autoimmune disorders 226
  • Wiskott-Aldrich Syndrome 226
  • Treatment of rheumatoid arthritis with stem cells 227
  • Treatment of Crohn's disease with stem cells 227
  • Stem cell transplants for scleroderma 228
  • Role of T Cells in immunological disorders 228
  • Autologous T cells from adult stem cells 229
  • Cell therapy for graft vs host disease 229
  • T cell infusion for suppressing GVHD 230
  • MSCs for GVHD 230
  • Cell therapy for viral infections 231
  • Anti-HIV ribozyme delivered in hematopoietic progenitor cells 231
  • Dendritic-cell targeted DNA vaccine for HIV 231
  • Manipulation of T cells for treatment of viral infections 231
  • T-cell therapy for CMV 231
  • T-cell therapy for HIV infection 232
  • T-cell immunity by Overlapping Peptide-pulsed Autologous Cells 233
  • Modification of iPSCs with a mutation to confer resistance to HIV 233
  • Cell therapy of lysosomal storage diseases 233
  • Niemann-Pick disease 234
  • Gaucher's disease 234
  • Fabry's disease 235
  • Cell therapy for diabetes mellitus 235
  • Limitations of current treatment 236
  • Limitations of insulin therapy for diabetes mellitus 236
  • Limitations of pancreatic transplantation 236
  • Islet cell transplantation 237
  • Autologous pancreatic islet cell transplantation in chronic pancreatitis 237
  • Clinical trials of pancreatic islet cell transplants for diabetes 237
  • Drawbacks of islet cell therapy 238
  • Use of an antioxidant peptide to improve islet cell transplantation 238
  • Cdk-6 and cyclin D1 enhance human beta cell replication and function 239
  • Devices for delivery of therapeutic cells in diabetes 239
  • Monitoring of islet cell transplants with MRI 240
  • Concluding remarks about allogeneic islet transplantation for diabetes 240
  • Encapsulation of insulin producing cells 240
  • Encapsulated porcine pancreatic islet cells for pancreas 240
  • Encapsulated insulinoma cells 241
  • Magnetocapsule enables imaging/tracking of islet cell transplants 241
  • Islet precursor cells 242
  • Dedifferentiation of β cells to promote regeneration 242
  • Pharmacological approaches for β cell regeneration 243
  • Xenotransplantation of embryonic pancreatic tissue 243
  • Non-pancreatic tissues for generation of insulin-producing cells 244
  • Exploiting maternal microchimerism to treat diabetes in the child 244
  • Bio-artificial substitutes for pancreas 244
  • Role of stem cells in the treatment of diabetes 245
  • Embryonic stem cells for diabetes 245
  • HSC transplantation to supplement immunosuppressant therapy 246
  • Insulin-producing cells derived from UCB stem cells 247
  • iPSc for diabetes 247
  • Pancreatic stem cells 247
  • Stem cell injection into portal vein of diabetic patients 249
  • Conversion of progenitor cells into insulin-producing cells 249
  • Human neural progenitor cells converted into insulin-producing cells 249
  • Isolation of islet progenitor cells 249
  • Pancreatic progenitor cells 250
  • Cell-based immunotherapy for type 1 diabetes 250
  • Dendritic cell-based therapy 250
  • T regulatory cell therapy for diabetes 251
  • Vaccine for diabetes 251
  • Gene therapy in diabetes 251
  • Viral vectors for gene therapy of diabetes 251
  • Genetically engineered dendritic cells 252
  • Genetically altered liver cells 252
  • Genetically modified stem cells 252
  • Companies developing cell therapy for diabetes 253
  • Concluding remarks about cell and gene therapy of diabetes 253
  • Cell therapy of gastrointestinal disorders 255
  • Inflammatory bowel disease 255
  • Cell therapy for liver disorders 255
  • Types of cells used for hepatic disorders 256
  • Methods of delivery of cells for hepatic disorders 256
  • Bioartificial liver 256
  • Hepatocyte-based artificial liver 257
  • Extracorporeal Liver Assist Device 257
  • Limitations of bioartificial liver 257
  • Proliferating cell-based bioartificial liver 258
  • Stem cells for hepatic disorders 258
  • Deriving hepatocytes from commercially available hMSCs 259
  • Implantation of hepatic cells derived from hMSCs of adipose tissue 259
  • Heterologous adult liver progenitor cells 259
  • Liver stem cell culture 259
  • MSC derived molecules for reversing hepatic failure 260
  • Cell-based gene therapy for liver disorders 260
  • Transplantation of genetically modified fibroblasts 261
  • Transplantation of genetically modified hepatocytes 261
  • Genetically modified hematopoietic stem cells 261
  • iPSCs derived from somatic cells for liver regeneration 261
  • Hepatocyte-like cells derived from human parthenogenetic stem cells 262
  • Clinical applications 262
  • Future prospects of cell-based therapy of hepatic disorders 263
  • Cell therapy of renal disorders 263
  • Bioartificial kidney 264
  • Cell-based repair for vascular access failure in renal disease 264
  • Mesangial cell therapy for glomerular disease 264
  • Stem cells for renal disease 265
  • Role of stem cells in renal repair 265
  • Bone marrow stem cells for renal disease 265
  • Human amniotic fluid stem cells for renal regeneration 266
  • MSC therapy for renal disease 266
  • Cell therapy for pulmonary disorders 266
  • Delivery of cell therapy for pumonary disorders 266
  • Intratracheal injection of cells for pulmonary hypoplasia 267
  • Role of stem cells in pulmonary disorders 267
  • Lung stem cells 267
  • Lung tissue regeneration from stem cells 267
  • Role of stem cells in construction of the Cyberlung 268
  • Respiratory epithelial cells derived from UCB stem cells 268
  • Respiratory epithelial cells derived from hESCs 269
  • Lung tissue engineering with adipose stromal cells 269
  • Cell-based tissue-engineering of airway 269
  • Pulmonary disorders that can be treatable with stem cells 270
  • Acute lung injury and ARDS treated with MSCs 270
  • Bronchopulmonary dysplasia treated with MSCs 271
  • Chronic obstructive pulmonary disease treated with MSCs 271
  • Cystic fibrosis treatment with genetically engineered MSCs 272
  • Lung regeneration by integrin α6β4-expressing alveolar epithelial cell 272
  • Pulmonary arterial hypertension treatment with EPCs 272
  • Cell therapy for disorders of bones and joints 273
  • Repair of fractures and bone defects 273
  • Adult stem cells for bone grafting 274
  • Bone regeneration by human very small embryonic-like (hVSEL) cells 274
  • Cell therapy for osteonecrosis 274
  • Cell therapy for radionecrosis 275
  • Cell therapy for cervical vertebral interbody fusion 275
  • Cell-mediated gene therapy for bone regeneration 275
  • ESCs for bone repair 275
  • hiPSCs for engineering personalized bone grafts 275
  • Intrauterine use of MSCs for osteogenesis imperfecta 276
  • In vivo bone engineering as an alternative to cell transplantation 276
  • In vivo differentiation of pluripotent stem cells for bone regeneration 276
  • MSCs for repair of bone defects 277
  • MSCs for repair of bone fractures 279
  • Osteocel 280
  • Stem cells for repairing skull defects 280
  • Stem cell-based bone tissue engineering 281
  • Spinal fusion using stem cell-based bone grafts 282
  • Osteoarthritis and other injuries to the joints 282
  • Mosaicplasty 283
  • Autologous cultured chondrocytes 283
  • Autologous intervertebral disc chondrocyte transplantation 284
  • Cartilage repair by genetically modified fibroblasts expressing TGF-β 285
  • Cartilage generation from stem cells 285
  • Cartilage engineering from iPSCs 286
  • Repair of osteonecrosis by bone marrow derived MSCs 287
  • Role of cell therapy in repair of knee cartilage injuries 287
  • Chondrocyte cell therapy 288
  • Meniscus-derived stem cells 288
  • Nanobiotechnology scaffolds for MSC-based cartilage reconstruction 289
  • Role of cells in the repair of anterior cruciate ligament injury 289
  • Autologous tenocyte implantation in rotator cuff injury repair 290
  • Platelet injection for tennis elbow 290
  • Cell therapy of rheumatoid arthritis 290
  • Cell therapy for diseases of the eye 291
  • Cell therapy for corneal repair 291
  • Stem cell therapy for limbal stem cell deficiency 293
  • Role of stem cells in fibrosis following eye injury 293
  • Stem cell transplantation for radiation sickness 293
  • MSCs for treatment of radiation damage to the bone 294
  • MSCs for regeneration of ovaries following radiotherapy damage 294
  • Cell therapy for wound healing 294
  • Cells to form skin substitutes for healing ulcers 295
  • CellSpray for wound repair 295
  • Cell therapy for burns 296
  • Closure of incisions with laser guns and cells 297
  • Genetically engineered keratinocytes for wound repair 297
  • Stem cells for skin regeneration 297
  • Follicular stem cells for skin and wound repair 297
  • MSCs for wound healing 298
  • Regeneration of aging skin by adipose-derived stem cells 298
  • Reprogramming autologous stem cells for wound regeneration 299
  • Role of amniotic fluid MSCs in repair of fetal wounds 299
  • Concluding remarks on regeneration of skin by stem cells 299
  • Cell therapy for regeneration 299
  • Cell therapy for regeneration of muscle wasting 299
  • Role of stem cells in regeneration of esophageal epithelium 300
  • Stem cells for regenerating organs 300
  • Stem cell-based regenerative therapy for xerostomia 301
  • Umbilical cord blood for regeneration 302
  • Role of cells in tissue engineering and reconstructive surgery 302
  • Scaffolds for tissue engineering 302
  • Improving vascularization of engineered tissues 303
  • Reconstruction of vasculature 303
  • Repair of aging skin by injecting autologous fibroblasts 303
  • Enhancing vascularization by combining cell and gene therapy 304
  • Nanobiotechnology applied to cells for tissue engineering 304
  • Choosing cells for tissue engineering 305
  • Stem cells for tissue repair 305
  • ESCs vs adult SCs for tissue engineering 306
  • Use of adult MSCs for tissue engineering 306
  • Stem cells for tissue engineering of various organs 307
  • Breast reconstruction by adipose tissue-derived stem cells 307
  • Engineering of healthy living teeth from stem cells 307
  • Intra-uterine repair of congenital defects using amniotic fluid MSCs 308
  • Skin regeneration by stem cells as an alternative to face transplant 309
  • Tissue engineering of bone by stem cells 309
  • Cell-based tissue engineering in genitourinary system 310
  • Urinary incontinence 310
  • Tissue engineering of urinary bladder 311
  • Label retaining urothelial cells for bladder repair 312
  • MSCs for bladder repair 312
  • Tissue-engineering of urethra using autologous cells 312
  • Repair of the pelvic floor with stem cells from the uterus 313
  • Reconstruction of vagina from stem cells 313
  • Reconstruction of cartilage for repair of craniofacial defects 313
  • Intraoperative cell therapy 313
  • Cell therapy for rejuvenation 314
  • Reversal of muscle weakness and atrophy in aging 314
  • Reversal of cognitive impairment in aging 315
  • Cell therapy for performance enhancement in sports 315
  • Application of stem cells in veterinary medicine 315
  • Use of stem cells to repair tendon injuries 315
  • Stem cells for spinal cord injury in dogs 316

5. Cell Therapy for Cardiovascular Disorders 317

  • Introduction to cardiovascular disorders 317
  • Limitations of current therapies for myocardial ischemic disease 317
  • Types of cell therapy for cardiovascular disorders 317
  • Cell-mediated immune modulation for chronic heart disease 319
  • Inducing the proliferation of cardiomyocytes 319
  • Pericardial origin of colony-forming units 319
  • Role of splenic myocytes in repair of the injured heart 320
  • Reprogramming of fibroblasts into functional cardiomyocytes 320
  • Stem cell-based therapies for cardiovascular diseases 321
  • Human cardiovascular progenitor cells 321
  • Human pluripotent stem cell-derived cardiomyocytes 322
  • Role of the SDF-1-CXCR4 axis in therapies for myocardial ischemia 322
  • Small molecules to enhance myocardial repair by stem cells 322
  • Stem cells and atherosclerosis 322
  • Cell therapy for atherosclerotic coronary artery disease 323
  • MyoCell™ (Bioheart) 323
  • Cardiac stem cells 324
  • Cardiomyocytes derived from epicardium 325
  • Methods of delivery of cells to the heart 325
  • Cellular cardiomyoplasty 325
  • IGF-1 delivery by nanofibers to improve cell therapy for MI 326
  • Non-invasive delivery of cells to the heart by Morph®guide catheter 326
  • Cell therapy for cardiac revascularization 326
  • Transplantation of cardiac progenitor cells for revascularization of myocardium 326
  • Stem cells to prevent restenosis after coronary angioplasty 327
  • Role of cells in cardiac tissue repair 327
  • Modulation of cardiac macrophages for repair of infarct 327
  • Transplantation of myoblasts for myocardial infarction 328
  • Patching myocardial infarction with fibroblast culture 329
  • Cardiac repair with myoendothelial cells from skeletal muscle 329
  • Myocardial tissue engineering 329
  • Role of stem cells in repair of the heart 330
  • Role of stem cells in cardiac regeneration following injury 330
  • Cardiomyocytes derived from adult skin cells 331
  • Cardiomyocytes derived from ESCs 331
  • Cardiomyocyte differentiation from hIPSCs 332
  • Studies to identify subsets of progenitor cells suitable for cardiac repair 333
  • Technologies for preparation of stem cells for cardiovascular therapy 333
  • Pravastatin for expansion of endogenous progenitor and stem cells 333
  • Cytokine preconditioning of human fetal liver CD133+ SCs 334
  • Expansion of adult cardiac stem cells for transplantation 334
  • Role of MSCs in growth of CSCs 334
  • Role of ESCs in repair of the heart 335
  • ESC transplantation for tumor-free repair of the heart 336
  • Transplantation of stem cells for myocardial infarction 336
  • Autologous bone marrow-derived stem cell therapeutics 336
  • Autologous bone marrow-derived mesenchymal precursor stem cells 337
  • Intracoronary infusion of mobilized peripheral blood stem cells 337
  • Transplantation of cord blood stem cells 338
  • Transplantation of hESCs 338
  • Transplantation of HSCs 338
  • Transplantation of autologous angiogenic cell precursors 339
  • Transplantation of adipose-derived stem cells 339
  • Transplantation of bone marrow-derived cells for myocardial infarct 340
  • Transplantation of human umbilical cord perivascular cells 341
  • Transplantation of endothelial cells 341
  • Transplantation of cardiomyocytes differentiated from hESCs 342
  • Stem cell therapy for cardiac regeneration 342
  • Regeneration of the chronic myocardial infarcts by HSC therapy 342
  • Human mesenchymal stem cells for cardiac regeneration 343
  • In vivo tracking of MSCs transplanted in the heart 344
  • MSCs for hibernating myocardium 344
  • Simultaneous transplantation of MSCs and skeletal myoblasts 344
  • Transplantation of genetically modified cells 345
  • Transplantation of genetically modified MSCs 345
  • Transplantation of cells secreting vascular endothelial growth factor 345
  • Transplantation of genetically modified bone marrow stem cells 345
  • Cell transplantation for congestive heart failure 345
  • AngioCell gene therapy for congestive heart failure 346
  • Injection of adult stem cells for CHF 347
  • Intracoronary infusion of cardiac stem cells 347
  • Myoblasts for treatment of congestive heart failure 347
  • Stem cell therapy for dilated cardiac myopathy 348
  • Role of cell therapy in cardiac arrhythmias 348
  • Prevention of myoblast-induced arrhythmias by genetic engineering 349
  • Stem cells as biological pacemakers 349
  • Stem cells for cardiac arrythmias 350
  • Ventricular tachycardia 350
  • ESCs for correction of congenital heart defects 351
  • Cardiac progenitors cells for treatment of heart disease 351
  • Autologus stem cells for chronic myocardial ischemia 352
  • Role of cells in cardiovascular tissue engineering 352
  • Construction of blood vessels with cells 352
  • Engineered arteries for bypass grafts 352
  • Fetal cardiomyocytes seeding in tissue-engineered cardiac grafts 353
  • Targeted delivery of endothelial progenitor cells labeled with nanoparticles 353
  • UCB progenitor cells for engineering heart valves 353
  • Cell-based in vitro regeneration of heart for transplantation 354
  • Cell therapy for peripheral vascular disease 354
  • ALD-301 354
  • Cell/gene therapy for PVD 355
  • Cell therapy for CLI in diabetics 355
  • Colony stimulating factors for enhancing peripheral blood stem cells 355
  • Intramuscular autologous bone marrow cells 356
  • Ixmyelocel-T cell therapy for critical limb ischemia 356
  • Stem cell-coated vascular grafts for femoral-tibial arterial bypass 356
  • Clinical trials of cell therapy in cardiovascular disease 357
  • Mechanism of the benefit of cell therapy for heart disease 359
  • A critical evaluation of cell therapy for heart disease 359
  • Publications of clinical trials of cell therapy for CVD 360
  • Current status of cell therapy for cardiovascular disease 360
  • Future directions for cell therapy of CVD 361
  • Combination of cells with biomedical scaffolds 361
  • Prospects of adult stem cell therapy for repair of heart 361
  • Role of cells in regeneration of the heart 362
  • Regeneration of cardiomyocytes without use of cardiac stem cells 362

6. Cell Therapy for Cancer 365

  • Introduction 365
  • Cell therapy technologies for cancer 365
  • Cell-based delivery of anticancer therapy 366
  • Cellular immunotherapy for cancer 366
  • Treatments for cancer by ex vivo mobilization of immune cells 367
  • Granulocytes as anticancer agents 367
  • Neutrophil granulocytes in antibody-based immunotherapy of cancer 368
  • Cancer vaccines 368
  • Autologous tumor cell vaccines 368
  • BIOVAXID 368
  • OncoVAX 369
  • Tumor cells treated with dinitrophenyl 369
  • Vaccines that simultaneously target different cancer antigens 369
  • Gene modified cancer cells vaccines 369
  • GVAX cancer vaccines 370
  • K562/GM-CSF 370
  • Active immunotherapy based on antigen specific to the tumor 371
  • The use of dendritic cells for cancer vaccination 371
  • Autologous dendritic cells loaded ex vivo with telomerase mRNA 371
  • Dendritic cell-targeted protein vaccines 372
  • Dendritic/tumor cell fusion 372
  • Genetically modified dendritic cells 372
  • In vivo manipulation of dendritic cells 373
  • Preclinical and clinical studies with DC vaccines 373
  • Vaccines based on dendritic cell-derived exosomes 374
  • Limitations of DC vaccines for cancer 374
  • Future developments to enhance clinical efficacy of DC vaccines 374
  • Lymphocyte-based cancer therapies 376
  • Adoptive cell therapy 376
  • Chimeric antigen receptor T cells 377
  • Combination of antiangiogenic agents with ACT 379
  • Expansion of antigen-specific cytotoxic T lymphocytes 379
  • Genetic engineering of tumor cells to activate T helper cells 379
  • CD8+ T cells for use in tumor immunotherapy 380
  • Tumor infiltrating lymphocytes 380
  • Hybrid cell vaccination 381
  • Chemoimmunotherapy 381
  • Stem cell-based anticancer therapies 381
  • Stem cell transplantation in cancer 381
  • Peripheral blood stem cell transplantation 382
  • Stem cell transplantation for hematological malignancies 384
  • Long-term results of HSC transplantation 385
  • Prediction of T-cell reconstitution after HSC transplantation. 385
  • HSC transplantation followed by GM-CSF-secreting cell vaccines 385
  • HSC transplantation for renal cell cancer 386
  • Complications of stem cell transplants in cancer 386
  • Graft-versus-host disease (GVHD). 386
  • Delayed immune reconstitution leading to viral infections and relapse 387
  • Tumor cell contamination 387
  • Neurological complications 387
  • Hepatic veno-occlusive disease 387
  • Current status and safety of allogeneic HSC transplantation 388
  • Complications of PBSC transplantation in children 388
  • Role of MSCs in cancer 389
  • MSC-mediated delivery of anticancer therapeutics 389
  • Nonmyeloablative allogeneic hematopoietic stem cell transplantation 390
  • Umbilical cord blood transplant for leukemia 390
  • hESC-derived NK cells for treatment of cancer 391
  • ESC vaccine for prevention of lung cancer 391
  • Genetic modification of stem cells for cancer therapy 392
  • Genetic modification of hematopoietic stem cells 392
  • Use of hematopoietic stem cells to deliver suicide genes to tumors 392
  • Delivery of anticancer agents by genetically engineered MSCs 392
  • Mesenchymal progenitor cells for delivery of oncolytic adenoviruses 393
  • Genetically modified NSCs for treatment of neuroblastoma 393
  • Innovations in cell-based therapy of cancer 394
  • Use of immortalized cells 394
  • Cancer therapy based on natural killer cells 394
  • Cytokine-induced killer cells 395
  • Mesothelin as a target for cancer immunotherapy 395
  • Nanomagnets for targeted cell-based cancer gene therapy 395
  • Implantation of genetically modified encapsulated cells for anticancer therapy 396
  • Antiangiogenesis therapy by implantation of microencapsulated cells 396
  • Recombinant tumor cells secreting fusion protein 396
  • A device for filtering cancer and stem cells in the blood 396
  • Cancer stem cells 397
  • Role of integrative nuclear signaling in stem cell development 397
  • Cancer stem cell markers 397
  • Breast cancer stem cells 398
  • Role of intestinal stem cells in intestinal polyposis 398
  • Role of endothelial progenitor cells in tumor angiogenesis 399
  • Role of cancer stem cells in metastases 399
  • Therapeutic implications of cancer stem cells 399
  • Targeting cancer stem cells in leukemia 400
  • - 15 -
  • Targeting cancer stem cells in ovarian cancer 401
  • Targeting cancer stem cells to screen anticancer drugs 401
  • Companies involved in cell-based cancer therapy 401
  • American Association for Cancer Research and ESCs 403
  • Future of cell-based immunotherapy for cancer 403

7. Cell Therapy for Neurological Disorders 405

  • Introduction 405
  • Use of stem cells for research in neurosciences 405
  • Cerebral organoids for modeling human brain development 405
  • Regeneration of the nervous system by endogenous stem cells 405
  • Molecular mechanism of neurogenesis 406
  • Generation of neurons from astroglia 406
  • In vivo cell replacement therapy by locally induced neural progenitor cells 407
  • Types of cells used for treatment of neurological disorders 407
  • Activated T lymphocytes 407
  • Differentiation of placenta-derived multipotent cells into neurons 408
  • Mesenchymal stem cells induced to secrete neurotrophic factors 408
  • Neural stem cells 408
  • Development of human CNS stem cells 408
  • Direct conversion of adult fibroblasts into neural progenitor cells 409
  • Distinction between NSCs and intermediate neural progenitors 410
  • Embryonic stem cell-derived neurogenesis 410
  • Epidermal neural crest stem cells for neurological disorders 410
  • Fusion of NSCs with endogenous neurons 411
  • Induction of NSCs from hESCs 411
  • Mechanism of migration of NSCs to sites of CNS injury 412
  • Monitoring of implanted NSCs labeled with nanoparticles 412
  • Neural progenitor cells 413
  • Neural stem cells in the subventricular zone of the brain 415
  • Oligodendrocyte progenitor cells 415
  • Promotion of neural stem cells expansion by betacellulin 415
  • Proteomics of neural stem cells 415
  • Regulation of neural stem cells in the brain 416
  • Role of CSF proteins in regulation of neural progenitor cells 417
  • Sequencing the transcriptomes of neural stem cells 417
  • Study of neural differentiation of hESCs by NeuroStem Chip 418
  • Transformation of neural stem cells into other cell types 418
  • Stem cell transplantation in the CNS 418
  • Development of CNS cells from non-CNS stem cells 418
  • Expansion of adult human neural progenitors 419
  • Hair-follicle stem cells for neural repair 419
  • NSCs for treatment of neurological disorders 420
  • NSCs and scaffolds for regeneration therapy of CNS disorders 420
  • Neurospheres 421
  • Stem cells from olfactory epithelium for transplantation in the CNS 421
  • Stem cells from human umbilical cord blood for CNS disorders 421
  • Choroid plexus cells for transplantation 422
  • Dental pulp cells for neuroprotection 422
  • Derivation of CNS cells from peripheral nervous system 422
  • Fetal tissue transplants 422
  • Immortalized cells for CNS disorders 423
  • Laboratory mice with human brain cells 424
  • Olfactory ensheathing cells for CNS repair 424
  • Ideal cells for transplantation into the nervous system 424
  • Cell therapy techniques for neurological applications 425
  • Carbon nanotubes to aid stem cell therapy of neurological disorders 425
  • Cells used for gene therapy of neurological disorders 425
  • Fibroblasts 425
  • Stem cells 426
  • Neuronal cells 426
  • Immortalized neural progenitor cells 426
  • Astrocytes 427
  • Cerebral endothelial cells 427
  • Human retinal pigmented epithelial cells 428
  • Enhancement of growth of stem cells in the brain by drugs 428
  • C3-induced differentiation and migration of NPC for repair of the brain 428
  • Stem cell therapies of neurological disorders combined with HBO 429
  • hESCs for CNS repair 429
  • Motor neurons derived from stem cells 429
  • MSCs for CNS repair 430
  • Neuronal differentiation of stem cells 431
  • Stem cells preparations for CNS disorders 431
  • Tracking of stem cells in the CNS by nanoparticles and MRI 432
  • Use of neural stem cells to construct the blood brain barrier 432
  • Methods of delivery of cells to the CNS 433
  • Engineered stem cells for drug delivery to the brain 433
  • Encapsulated cells 433
  • CNS delivery of cells by catheters 434
  • CNS neotissue implant 434
  • Intrathecal delivery of stem cells 434
  • Intravascular administration 435
  • Neural stem cells as therapeutic delivery vehicles 436
  • Neurological disorders amenable to cell therapy 436
  • Neuroprotection by cell therapy 436
  • Cells secreting neuroprotective substances 437
  • Stem cells for neuroprotection 437
  • Neuroprotection by intravenous administration of HSCs 437
  • Human UCB-derived stem cells for the aging brain 437
  • hESC transplantation to prevent cognitive impairment from radiation 438
  • Neurodegenerative disorders 438
  • MSCs for therapy of neurodegenerative disorders 438
  • Role of stem cells in neurodegenerative disorders 439
  • Role of NSCs in disorders associated with aging brain 440
  • NSCs for improving memory 440
  • Parkinson's disease 441
  • Cell therapies for PD 441
  • Delivery of cells for PD 442
  • Dopamine neurons for PD 442
  • Graft survival-enhancing drugs 443
  • Encapsulated cells for PD 443
  • Stem cell transplantation in animal models of PD 444
  • Trials of stem cell transplantation in PD patients 445
  • Stem cells for production of glial derived neurotrophic factor 447
  • Potential of regeneration of endogenous stem cells in PD 447
  • Human retinal pigment epithelium cells for PD 447
  • Tumorigenic potential of transplantated dopaminergic hESCs 448
  • Transplantation of embryonic medial ganglionic eminence cells 448
  • Xenografting porcine fetal neurons 449
  • Personalized stem cell therapy for PD 449
  • MSCs for multiple system atrophy 450
  • Cell therapy for Huntington's disease 450
  • Fetal striatal cell transplantation 450
  • Transplantation of encapsulated porcine choroids plexus cells 451
  • iPSCs for HD 451
  • Mobilization of endogenous neural progenitor cells in HD 451
  • Cell therapy for Alzheimer's disease 451
  • Choroid plexus epithelial cells for AD 452
  • Implantation of genetically engineered cells producing NGF 452
  • Implantation of stem cells derived from the skin 453
  • Neural stem cell implantation for Alzheimer's disease 453
  • Cell therapy for amyotrophic lateral sclerosis 453
  • Stem cell techniques for study of ALS 454
  • Use of stem cells for ALS 454
  • Transplantation of glial restricted precursors in ALS 456
  • Stem cell-based drug discovery for ALS 456
  • Cell therapy for demyelinating disorders 457
  • Autologous bone marrow stem cell therapy for multiple sclerosis 457
  • ESCs for remyelination 458
  • Fusokine method of personalized cell therapy of MS 458
  • Genetically engineered macrophages expressing NaV1.5 458
  • Hematopoietic stem cell transplantation for MS 459
  • Mechanism of repair of demyelination after NSC transplantation 459
  • MSCs for multiple sclerosis 460
  • Neural progenitor cells for neuroprotection in MS 460
  • T cell-based personalized vaccine for MS 461
  • Stem cells for chronic inflammatory demyelinating polyneuropathy 461
  • Stem cell transplantation for Pelizaeus-Merzbacher disease 461
  • X-linked adrenoleukodystrophy 461
  • Cell therapy of stroke 462
  • Adult stem cell therapy in stroke 462
  • Implantation of genetically programmed ESCs 463
  • Intravenous infusion of MSCs 463
  • Intravenous infusion of human UCB stem cells 464
  • Intracerebral administration of human adipose tissue stromal cells 465
  • Neural stem cell therapy for stroke 465
  • Transplantation of encapsulated porcine choroids plexus 466
  • Transplantation of fetal porcine cells 467
  • Role of cell therapy in management of stroke according to stage 467
  • Clinical trials of cell therapy for stroke 467
  • Future of cell therapy for stroke 469
  • Cell therapy of traumatic brain injury 470
  • Cell/gene therapy for TBI 470
  • Clinical trials of autologous stem cell therapy for TBI 470
  • Limitations of stem cell therapy for acute TBI 471
  • Improving the microenvironments of transplanted cells in TBI 471
  • Cell therapy for spinal cord injury 472
  • Autoimmune T cells against CNS myelin-associated peptide 472
  • Fetal neural grafts for SCI 472
  • Olfactory-ensheathing cells for SCI 472
  • Oligodendrocyte precursor cells for treatment of SCI 473
  • Schwann cell transplants for SCI 473
  • Transplantation of glial cells for SCI 473
  • Stem cells for SCI 474
  • Bone marrow stem cells for SCI 474
  • Embryonic stem cells for SCI 474
  • Transplantation of induced pluripotent stem cells in SCI 475
  • Transplantation of MSCs for SCI 475
  • Transplantation of NSCs for SCI 476
  • Transplantation of human dental pulp stem cells 476
  • Transdifferentiation of BM stem cells into cholinergic neurons for SCI 477
  • Evaluation of experimental studies of stem cell transplantation in SCI 477
  • Spinal stem cells for treatment of ischemic injury of spinal cord 477
  • Combined approaches for regeneration in SCI 478
  • Combined cell/gene therapy for SCI 478
  • Delivery of cells in SCI 479
  • Intrathecal injection of cells labeled with magnetic nanoparticles 479
  • Intravenous injection of stem cells for spinal cord repair 479
  • Clinical applications of stem cells for SCI 479
  • Autologous bone marrow cell transplantation for SCI 480
  • Cell therapy of syringomyelia 480
  • Cell therapy for neurogenetic disorders 480
  • Hurler's syndrome treated with stem cells 480
  • Krabbe's disease treated with UCB stem cells 481
  • Krabbe's disease treated with combination of cell and gene therapy 481
  • Mitochondrial encephalomyopathies treated with stem cells 482
  • Sanfilippo syndrome type B treated with UCB stem cells 482
  • Cell therapy for lysosomal storage disorders 483
  • Cell therapy for Batten disease 483
  • Cell/gene therapy for Farber's disease 483
  • Genetically modified HSCs for metachromatic leukodystrophy 484
  • Neural stem cells for lysosomal storage disorders 484
  • Cell therapy of epilepsy 484
  • Cell therapy of posttraumatic epilepsy 485
  • Cell therapy for temporal lobe epilepsy 485
  • Cell therapy for pharmacoresistant epilepsies 486
  • Cell therapy for developmental neurological disorders 486
  • Cell therapy for cerebral palsy 486
  • Cell-based therapies for malignant brain tumors 487
  • Bone morphogenetic protein for inhibition of glioblastoma multiforme 487
  • Dendritic cell therapy for brain tumors 487
  • Encapsulated cells for brain tumors 488
  • Immunotherapy of GBM targeting cancer stem cells 489
  • Mesenchymal stem cells for the treatment of gliomas 489
  • Neural stem cells for drug/gene delivery to brain tumors 489
  • Role of cancer stem cells in resistance to radiotherapy 491
  • Stem cell-based therapy targeting EGFR in GBM 491
  • Targeting stem cells in brain tumors 491
  • Clinical trials of cell therapy of glioblastoma multiforme 492
  • Cell therapy for muscle disorders 492
  • Duchenne muscular dystrophy 492
  • Combination of cell and pharmacotherapy for DMD 492
  • Myoblast transplant for DMD 493
  • Myoblast-based gene transfer 493
  • Myoblasts lacking the MyoD gene 494
  • Myoblast injection for treatment of other muscular dystrophies 494
  • Role of satellite cells in the treatment of DMD 494
  • Stem cells for DMD 495
  • Wnt7a treatment for DMD 496
  • Cell therapy for autism 497
  • Management of chronic intractable pain by cell therapy 497
  • Implantation of chromaffin cells 497
  • Role of stem cells in management of pain 498
  • Implantation of astrocytes secreting enkephalin 498
  • Cells for delivery of antinociceptive molecules 499
  • Implantation of genetically engineered cells 499
  • Cell therapy for low back pain 499
  • Cell therapy for neuropathic itch 500
  • Cell therapy for neuroendocrine disorders 500
  • Pituitary stem cells 500
  • Cell therapy for retinal degenerative disorders 500
  • Adipose-derived stem cells for retinal degeneration 501
  • Delivery of CNTF by encapsulated cell intraocular implants 501
  • ESCs for retinal degenerative disorders 502
  • Genetically engineered retinal pigmented epithelial cell lines 502
  • hESC-derived RPE cells for macular dystrophy 502
  • Human retinal stem cells 503
  • iPSCs for AMD 503
  • Neuroprotective effect of neural progenitor cell transplantation 504
  • Stem cell transplantation in the retina 504
  • Combining cell and gene therapies for retinal disorders 505
  • Stem cell therapy for hearing loss 505
  • Cell thery for peripheral nerve lesions 505
  • Cell transplants for peripheral nerve injuries 505
  • Role of adipose-derived stem cells in peripheral nerve regeneration 506
  • Treatment of diabetic neuropathy with endothelial progenitor cells 506
  • Complications of cell therapy of neurological disorders 506
  • Tumor formation after CNS transplantation of stem cells 507
  • Uncontrolled differentiation of implanted cells 507
  • Donor stem cell-derived brain tumor 507
  • Tumorigenicity of ESC-derived retinal progenitor cells 507
  • Clinical trials of cell therapy in neurological disorders 508
  • Future prospects for cell therapy of CNS disorders 509

8. Ethical, Legal and Political Aspects of Cell therapy 511

  • Introduction 511
  • Political and ethical aspects of hESC research in the US 511
  • Ethical issues concerning fetal tissues 511
  • Morality and hESC research 511
  • Opponents of hESC research in the US 512
  • Use of hESCs in NIH-supported research 513
  • Politics of hESC research in the US 514
  • Public opinion in the US about hESC research 516
  • Human stem cell cloning in the US 517
  • Stem cell guidelines of various US institutions 518
  • Ethics of transplanting human NSCs into the brains of nonhuman primates 518
  • ESC lines available worldwide 519
  • ESC policies around the world 520
  • Countries with no defined policies on hESC research 520
  • Australia 521
  • Canada 521
  • China 522
  • Denmark 523
  • France 523
  • Germany 523
  • India 525
  • Ireland 526
  • Israel 526
  • Italy 526
  • Japan 527
  • The Netherlands 527
  • Saudi Arabia 528
  • Singapore 528
  • South Africa 529
  • South Korea 529
  • Spain 529
  • Sweden 530
  • Switzerland 530
  • United Kingdom 531
  • UK StemCellBank 531
  • European Union 532
  • EU guidelines for stem cell research 532
  • European stem cell bank 534
  • EMBO's recommendations for stem cell research 534
  • Public opinion in Europe about hESC research 535
  • United Nations, cloning and nuclear transfer 536
  • The Embryo Project for information on ESC research 536
  • Concluding remarks about ethics of ESC research 536
  • Ethical issues concerning umbilical cord blood 537
  • Legal issues associated with stem cells 537
  • Stem cell patents 537
  • Stem cell patents in the United States 537
  • Current status of Thomson patents at WARF 538
  • Stem cell patents in the European Union 538
  • Cell therapy tourism 539

9. Safety and Regulatory Aspects of Cell Therapy 541

  • Introduction 541
  • Safety issues of cell therapy 541
  • Immune-mediated reactions to transpanted stem cells 541
  • Human virus infections associated with stem cell transplantation 542
  • Herpes simplex virus type 1 542
  • Cytomegalovirus 542
  • Opportunistic infections among hematopoietic stem cell transplant recipients 542
  • Cord colitis syndrome 542
  • Carcinogenic potential of stem cells and its prevention 543
  • FDA safety regulations for cell and tissue products 543
  • FDA Guidance on license applications for umbilical cord blood products 544
  • Regulation of cord blood banks in the US 544
  • Regulatory issues for biotechnology-derived drugs 544
  • Regulation of cell selection devices for PBSCs at point of care 545
  • FDA rules for human cells and tissues 546
  • FDA regulation of fetal cellular or tissue products 546
  • FDA and ESC lines 547
  • FDA and clinical trials using hESCs 547
  • Cell and gene therapy INDs placed on hold by the FDA 548
  • Regulatory issues for genetically engineered cell transplants 548
  • FDA guidelines for human tissue transplantation 549
  • FDA considers cultured stem cells for therapy as drugs 549
  • Xenotransplantation 549
  • Clinical Protocol Review and Oversight 549
  • Informed consent and patient education 550
  • Xenotransplantation product sources 550
  • FDA guidelines for xenografts 550
  • Regulatory challenges for the clinical use of cell products 552
  • Regulations relevant to cell therapy in the European Union 552
  • Regulations about use of stem cells in the EU 554
  • Guidelines for cell therapy in the UK 554
  • NIH and stem cells 555
  • hESC lines approved under the new NIH guidelines 555
  • Clinical trials in cell therapy 555

Tables

  • Table 1-1: Landmarks in the history of cell therapy 29
  • Table 1-2: Examples of cells involved in various diseases 34
  • Table 2-1: Types of human cells used in cell therapy 39
  • Table 2-2: A selection of companies providing cell culture media 43
  • Table 2-3: A sampling of companies supplying cell sorters 49
  • Table 2-4: Companies involved in cell-based drug discovery 58
  • Table 2-5: Methods of delivery of cells for therapeutic purposes 60
  • Table 2-6: Therapeutic applications of encapsulated cells 64
  • Table 2-7: Companies working on encapsulated cell technology 67
  • Table 2-8: Molecular imaging methods for tracking cells in vivo 72
  • Table 3-1: Various levels of potency relevant to stem cells 80
  • Table 3-2: Companies involved in cord blood banking as a source of stem cells 110
  • Table 3-3: Comparison of techniques for nuclear reprogramming of stem cells 114
  • Table 3-4: Banks of patient-specific iPSC lines 119
  • Table 3-5: Companies providing iPSCs 119
  • Table 3-6: Sources of adult human stem cells 124
  • Table 3-7: Comparison of human stem cells according to derivation 134
  • Table 3-8: Enhancing engraftment, mobilization and expansion of stem cells 154
  • Table 3-9: Applications of stem cells 171
  • Table 3-10: Advantages and limitations of methods for optimizing MSCs 183
  • Table 3-11: Pharmaceutical manipulation of stem cells 189
  • Table 3-12: Growth factors with positive effects on stem cells and applications 191
  • Table 3-13: Examples of drugs that induce granulocytopenia at stem cell level 202
  • Table 3-14: Academic institutes involved in stem cell research 210
  • Table 3-15: Companies involved in stem cell technologies 211
  • Table 4-1: Therapeutic applications of regulatory T cells (T-regs) 228
  • Table 4-2: Various tissue/cell therapy approaches to the treatment of type 1 diabetes 235
  • Table 4-3: Companies involved in cell therapy for insulin-dependent diabetes 253
  • Table 4-4: Major pulmonary disorders potentially treatable by stem cell manipulation 270
  • Table 4-5: Cell-based repair of knee cartilage damage 287
  • Table 4-6: Intraoperative cell therapy 314
  • Table 5-1: Classification of various types of cell therapy for cardiovascular disorders 318
  • Table 5-2: Clinical trials of cell therapy in cardiovascular disease 357
  • Table 6-1: Cell therapy technologies used for cancer 365
  • Table 6-2: Companies involved in developing cell-based therapies for cancer 401
  • Table 7-1: NSCs-based approaches for neurological disorders. 420
  • Table 7-2: Experimental use of immortalized cells for CNS disorders 423
  • Table 7-3: Combination of stem cells and HBO in models of neurological disorders 429
  • Table 7-4: Therapeutic applications of MSCs for neurological disorders 430
  • Table 7-5: Methods for delivering cell therapies in CNS disorders 433
  • Table 7-6: Neurological disorders amenable to cell therapy 436
  • Table 7-7: Types of cell used for investigative treatment of Parkinson's disease 441
  • Table 7-8: Status of cell therapies for Parkinson's disease 442
  • Table 7-9: Role of cell therapy in management of stroke according to stage 467
  • Table 7-10: Clinical trials of cell therapy for stroke: completed, ongoing and pending 467
  • Table 7-11: Clinical trials with cell-based therapies in neurological disorders (excluding stroke) 508
  • Table 8-1: Listed numbers of ESC lines around the world 519
  • Table 8-2: Stem cell policies around the world 520
  • Table 8-3: European public attitudes about research involving human stem cells 535
  • Table 9-1: Possible adverse reactions and safety issues of cell therapy 541

Figures

  • Figure 1-1: Interrelationships of cell therapy to other technologies 32
  • Figure 1-2: Interrelationships of gene, cell and protein therapies 33
  • Figure 1-3: Engineering of RBCs for drug delivery 37
  • Figure 3-1: A simplified biological scheme of embryonic stem Cells 80
  • Figure 3-2: Steps of iPS cell production 115
  • Figure 3-3: hESC-derived by somatic cell nuclear transfer 151
  • Figure 3-4: Flow chart of development of stem cells with potential bottlenecks 217
  • Figure 4-1: Reprograming ESCs/iPSCs cells to β-cells for type 1 diabetes 249
  • Figure 5-1: Ex vivo vs in vivo approaches to regeneration of the heart 318
  • Figure 5-2: hESC-derived cardiomyocytes from laboratory to bedside 331
  • Figure 5-3: Steps in growing a new heart in vitro for transplantation 354
  • Figure 6-1: A scheme of generation and administration of tumor antigen-pulsed dendritic cells 375
  • Figure 6-2: Stem cell transplantation techniques 383
  • Figure 7-1: Stem cells that can give rise to neurons 414
  • Figure 7-2: Scheme of iPSCs for personalized cell therapy of Parkinson disease 449
  • Figure 7-3: Approaches to stem cell therapy in stroke 463

Part II

10. Markets and Future Prospects for Cell Therapy 6

  • Introduction 6
  • Methods for estimation of cell therapy markets 6
  • Potential markets for cell therapy 7
  • Markets according to technologies 7
  • Stem cell transplants 7
  • Supporting cell technologies 8
  • Blood transfusion market 8
  • Cord blood collection and storage 8
  • Cell therapy and related technologies 8
  • Cell therapy markets according to therapeutic area 8
  • Bone and joint disorders 9
  • Cancer 9
  • Cardiovascular disorders 10
  • Diabetes mellitus 10
  • Liver disorders 11
  • Neurological disorders 11
  • Retinal degenerative diseases market 12
  • Skin and wound care 12
  • Urinary incontinence 12
  • Reconstruction of teeth by stem cell implants 12
  • Market size according to geographical areas 13
  • Unmet market needs in cell therapy 14
  • Drivers of growth of cell therapy markets 14
  • Role of stem cells in regenerative medicine 14
  • Role of cells in markets for artificial organs 15
  • Increase of R&D expense on cell therapy 15
  • Increased used of cell-based drug discovery 15
  • Impact of emerging healthcare trends on cell therapy markets 15
  • Markets for cell therapy tourism 15
  • Involvement of pharmaceutical companies in cell therapy 16
  • Future prospects of cell therapy 16
  • Embryonic stem cell research around the world 16
  • Consortia for ESC research in Europe 17
  • EuroStemCell 17
  • FunGenES 18
  • ESTOOLS 18
  • UK National Stem Cell Network 19
  • Ethical concerns about commercialization of embryonic stem cells 20
  • Education of the physicians 20
  • Public education 20
  • NIH support of stem cell research 20
  • Funding of stem cell research from non-federal sources 21
  • Prospects of venture capital support for stem cell companies 22
  • Cell therapy in the developing countries 23
  • Guidelines for stem cell therapies 24
  • Business strategies 24
  • Formation of networks 25
  • Market potential of autologous vs allogeneic cells 25
  • Future market potential of adult vs embryonic stem cells 26

11. Companies Involved in Cell Therapy 28

  • Introduction 28
  • Profiles of selected companies 30
  • Collaborations 347

12. Academic Institutions 357

  • Introduction 357
  • Stem cell center 357
  • Profiles of institutions 358
  • Collaborations 447

13. References 451

Tables

  • Table 10-1: Market size according to cell therapy and related technologies 2013-2023 7
  • Table 10-2: Market size according to therapeutic areas for cell therapy in 2013-2023 9
  • Table 10-3: Cell therapy markets for cardiovascular disorders in 2013-2023 10
  • Table 10-4: Values of cell therapies for neurological disorders in 2013-2023 11
  • Table 10-5: Total cell therapy market in 2013-2023 according to geographical areas 13
  • Table 10-6: Cord blood market according to geographical areas 2013-2023 13
  • Table 10-7: Stem cells transplant market according to geographical areas 2013-2023 13
  • Table 10-8: SWOT Autologous cells vs allogeneic cells 25
  • Table 11-1: Publicly traded cell therapy companies 28
  • Table 11-2: Selected collaborations of cell therapy companies 347
  • Table 12-1: Therapeutic uses of stem cells 365
  • Table 12-2: Commercial collaborations of US academic institutes relevant to stem cells 447

Figures

  • Figure 10-1: Unmet needs in cell therapy 14
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