Cell Therapy - Technologies, Markets and Companies - This report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine.

	Cell Therapy - Technologies, Markets and Companies
	0. Executive Summary ......... 19 1. Introduction to Cell Therapy................... 23 Introduction.. 23 Historical landmarks of cell therapy............. 23 Interrelationship of cell therapy technologies..................... 25 Cells and organ transplantation ................... 25 Cells and protein/gene therapy ................... 26 Cell therapy and regenerative medicine ....... 27 Cells therapy and tissue engineering ........... 27 Therapy based on cells involved in disease .. 28 Advantages of therapeutic use of cells......... 28 Use of cells for improving drug delivery....... 29 2. Cell Therapy Technologies ...................... 31 Introduction.. 31 Cell types used for therapy ... 31 Sources of cells ..................... 31 Xenografts ...32 Cell lines ......32 Immortalized cells...........32 Blood component therapy......32 Therapeutic apheresis......32 Leukoreduction ...............33 Platelet therapy ..............33 Basic technologies for cell therapy............... 34 Cell culture...34 Companies involved in cell culture............34 Cell sorting...36 Flow cytometry ...............36 A dieltectrophoretic system for cell separation ..................37 Companies supplying cell sorters..............37 Dynabead technology for cell sorting .............38 ALDESORTER system for isolation of stem cells......................38 Preservation of cells .............38 Packaging of cells.................39 Selective expansion of T cells for immunotherapy...................39 Cloning and cell therapy........39 Techniques for cell manipulation ...................40 Cell-based drug discovery..... 40 Cells as vehicles for drug delivery................ 42 Drug delivery systems for cell therapy......... 43 Devices for delivery of cell therapy ................43 Artificial cells . 44 Applications of artificial cells ..44 Cell encapsulation................. 44 Diffusion capsule for cells......45 Encapsulated cell biodelivery .45 Therapeutic applications of encapsulated cells.45 Nitric oxide delivery by encapsulated cells......47 Implantation of microencapulated genetically modified cells ....47 Ferrofluid microcapsules for tracking with MRI 48 Companies involved in encapsulated cell technology ...............48 Electroporation ..................... 49 Gene therapy . 49 Cell-mediated gene therapy...50 Fibroblasts .....................50 Chondrocyte...................51 Skeletal muscle cells........51 Vascular smooth muscle cells...................52 Keratinocytes..................52 Hepatocytes ...................52 Lymphocytes ..................52 Mammalian artificial chromosomes ...........53 In vivo tracking of cells......... 53 Molecular imaging for tracking cells ...............54 MRI technologies for tracking cells............54 - 4 - Superparamagnetic iron oxide nanoparticles as MRI contrast agents...........54 Visualization of gene expression in vivo by MRI.................55 Role of nanobiotechnology in development of cell therapy . 55 Cell transplantation for development of organs .................. 56 Cells transplantation and tolerance.............. 56 Strategies to improve tolerance of transplanted cells ..............56 Encapsulation to prevent immune rejection ......................57 Prevention of rejection of xenotransplants.57 3. Stem Cells. 59 Introduction.. 59 Biology of stem cells ............. 59 Embryonic stem cells............59 Growth and differentiation of ESCs ................60 Regulation of stem cell self-renewal and differentiation ......60 Role of Pax3 in stem cell differentiation.....61 ESCs and signaling pathways...................61 Genetic signature of of stem cells.............62 Epigenetics of hESCs .......62 Chromatin as gene regulator for ESC development ............63 Mechanism of differentiation of ESCs ........63 Comparison of development of human and mouse ESCs.....63 In vitro differentiation of hESCs ...............64 hESCs in stead of oocytes for reprogramming human somatic nuclei ..........64 Mechanism of regulation of stem cells for regeneration of body tissues ............64 Parthenogenesis and human stem cells..........65 Uniparental ESCs ............66 Bone marrow stem cells........66 Hematopoietic stem cells..67 Role of HSCs in the immune system .........68 Mesenchymal stem sells...68 Multipotent adult progenitor cells .............69 Side population (SP) stem cells................70 Differentiation of adult stem cells ..................70 Growth and differentiation of HSCs................72 Signaling pathways in the growth and differentiation of HSCs ....................72 Mathematical modeling of differentiation of HSCs ..............72 Role of prions in self renewal of HSCs .......73 Sources of stem cells ............ 73 Sources of of human embryonic stem cells .....73 Nuclear transfer to obtain hESCs...................73 Direct derivation of hESCs from embryos without nuclear transfer...................74 Alternative methods of obtaining hESCs.........75 Establishing hESC lines without destruction of embryo .......75 Altered nuclear transfer ...76 Small embryonic-like stem cells ...............76 Advantages and disadvantages of ESCs for transplantation .....76 Use of ESC cultures as an alternative source of tissue for transplantation.........77 Spermatogonial stem cells.....78 Amniotic fluid as a source of stem cells ..........78 Placenta as source of amnion-derived multipotent progenitor cells ..................79 Umbilical cord perivascular cells as a source of MSCs..............79 Umbilical cord blood as source of neonatal stem cells .............80 Cryopreservation of cord blood stem cells .81 Applications of cord bood .81 Advantages of cord blood .81 Limitations of the use of cord blood ..........82 Controversies involving cord blood ...........83 Infections following cord blood transplants 83 Unanswered questions about cord blood transplantation ....84 Companies involved in cord blood banking 84 UCB banking in the UK.....85 US national UCB banking system..............85 Future prospects of cord blood as a source of stem cells ....86 Sources of adult human stem cells............... 87 Adipose tissue as a source of stem cells .........87 Skin as a source of stem cells88 Follicle stem cells ............88 Mesenchymal stem cells in skin................89 Epidermal neural crest stem cells .............89 Regulation of stem cells in hair follicles .....89 - 5 - Controlling the maturation of embryonic skin stem cells.....90 Stem cells in teeth ...............90 Peripheral blood stem cells ....91 Spleen as a source of adult stem cells............91 Search for master stem cells .92 Adult stem cells vs embryonic stem cells ..... 92 Transdifferentiation potential of adult stem cells ....................92 Neural crest stem cells from adult hair follicles93 Stem cells obtained from blood in adults........94 Pluripotent stem cells derived from human somatic cells ... 94 VENT cells ...... 95 Stem cell technologies .......... 95 Analysis of stem cell growth and differentiation......................95 Stem cell biomarkers ............95 Endoglin as a functional biomarker of HSCs ......................96 STEMPROÒ EZChekä for analysis of biomarkers of hESCs ..96 SSEA-4 as biomarker of MSCs..................96 p75NTR as a biomarker to isolate adipose tissue-derived stem cells ...........96 Neural stem cell biomarker......................97 Protein expression profile as biomarker of stem cells .........97 Gene inactivation to study hESCs..................97 RNAi to study gene inactivation in hESCs ..98 Study of ESC development by inducible RNAi....................98 Targeting Induced Local Lesions in Genomes ....................99 Homologous recombination of ESCs..........99 Immortalization of hESCs by telomerase ...99 miRNA and stem cells ......... 100 Role of miRNAs in gene regulation during stem cell differentiation............ 100 Influence of miRNA on stem cell formation and maintenance ................... 100 Stem cells and cloning ........ 101 Cell nuclear replacement and cloning...... 101 Nuclear transfer and ESCs..................... 101 Cloning from differentiated cells ............. 103 Cloning mice from adult stem cells ......... 103 Creating interspecies stem cells ............. 104 Cloned cells for transplantation medicine. 104 Claims of cloning of hESCs .................... 104 Engraftment, mobilization and expansion of stem cells ......... 106 Enhancement of HSC engraftment by calcium-sensing receptor ............... 106 Stem cell mobilization by hyperbaric oxygen................... 107 Mobilization of HSCs by growth factors.... 107 Mobilization of adult human HSCs by use of inhibitors...... 108 Ex vivo expansion of human HSCs in culture................... 109 Expansion of HSCs in culture by inhibiting aldehyde dehydrogenase ......... 109 Expansion of adult stem cells by activation of Oct4.......... 110 Selective Amplification ... 110 Antisense approach for preservation and expansion of stem cells ............. 110 Mobilization by adenoviral vectors expressing angiogenic factors.............. 111 Stem cell mobilization by acetylcholine receptor agonists . 111 Expansion of transduced HSCs in vivo..... 112 Use of parathyroid hormone to increase HSC mobilzation . 112 Expansion of stem cells in vivo by Notch receptor ligands. 112 Technologies for inducing differentiation of stem cells........... 112 Growth factor-induced differentiation of MAPCs............... 112 Neurotrophin-mediated survival and differentiation of hESCs ................... 113 Generation of RBCs from hematopoietic stem cells .......... 113 Use of RNAi to expand the plasticity of autologous adult stem cells........... 113 Use of carbohydrate molecules to induce differentiation of stem cells........ 114 Mechanical strain to induce MSC differentiation............... 114 Limitations of the currently available stem cell lines in the US 114 Contaminating material in stem cell culture and measures to eliminate it ....... 115 Stem cell separation ........... 116 Stem cell culture................ 117 Conversion of stem cells to functioning adipocytes ............... 117 Mass production of ESCs ..... 117 Promoting survival of dissociated hESCs....... 118 Analysis and characterization of stem cells ... 118 Labeling of stem cells ......... 118 Quantum dots for labeling hMSCs........... 119 Quantum dot imaging for ESCs .............. 119 Perfluorocarbon nanoparticles to track therapeutic cells in vivo ................ 119 - 6 - Applications of stem cells.... 120 Controlling the maintenance process of hematopoietic stem cells .................. 120 Peripheral blood stem cell transplantation .... 121 Complications of PBSC transplantation in children ........... 121 Stem cell transplantation for radiation sickness............... 121 Stem cells and human reproduction............. 122 Expansion of spermatogonial stem cells .. 122 Conversion of ESCs into spermatogonial stem cells.......... 122 Conversion of stem cells to oocytes ........ 122 ESCs for treatment of infertility in women ...................... 123 Cloning human embryos from oocytes matured in the laboratory ............. 123 In utero stem cell transplantation........... 124 Innovations in delivery of stem cells ............ 125 Immunological aspects of hESC transplantation ................... 125 Stem cells for organ vascularization............. 126 Activation of EphB4 to enhance angiogenesis by EPCs...... 126 Biofusion by genetically engineering stem cells .................... 127 Stem cell gene therapy ....... 127 Therapeutic applications for hematopoietic stem cell gene transfer ........... 127 Use of hematopoietic stem cells for gene therapy............ 127 Molecular vibration for gene transfer ...... 128 Use of lentiviral vectors for in vivo gene transfer to stem cells ................. 128 Use of mesenchymal stem cells for gene therapy ............ 129 Gene targeting of stem cells .................. 129 Regulation of gene expression for SC-based gene therapy 129 Stem cells and in utero gene therapy...... 130 Gene delivery to stem cells by artificial chromosome expression .............. 130 Linker based sperm-mediated gene transfer technology... 130 Combination of gene therapy with nuclear transfer.......... 131 The future of hematopoietic stem cell gene therapy......... 131 Stem cell pharmaceutics ..... 131 Stem cells for drug discovery................. 131 Advantages of using stem cells for drug discovery........... 132 Role of stem cells in therapeutic effects of drugs ............. 132 Hepatocytes derived from hESCs............ 132 Cardiomyocytes derived from hESCs....... 133 ESCs as source of models for drug discovery .................. 134 Engineered stem cells for drug delivery to the brain ........ 134 Use of ESCs for toxicology and drug safety studies .......... 135 Stem Cells for Safer Medicines Consortium ..................... 136 Pharmaceutical manipulation of stem cells...................... 136 Adverse effects of drugs on stem cells .... 137 Future challenges for stem cell technologies .................... 138 Study of the molecular mechanism of cell differentiation ....... 138 MBD3-deficient ESC line...... 138 In vivo study of human hemopoietic stem cells .................... 139 Stem cell biology and cancer ...................... 139 Formation of teratomas following ESC transplants ................ 140 Research into plasticity of stem cells from adults.................. 140 Stem cells and aging .......... 140 Activation of bone marrow stem cells into therapeutic cells ... 141 Role of nitric oxide in stem cell mobilization and differentiation ..................... 141 Stem cell genes ................. 142 Gene expression in hESCs ..................... 142 The casanova gene in zebrafish.............. 142 Nanog gene.................. 143 Stem cell proteomics .......... 144 Proteomic studies of mesenchymal stem cells ................. 144 Proteomic profiling of neural stem cells ... 145 Proteome Biology of Stem Cells Initiative 145 Genomic alterations in cultured hESCs ......... 145 Hybrid embryos/cybrids for stem cell research..................... 146 Generation of patient-specific pluripotent stem cells ............. 146 Markers for characterizing hESC lines .......... 147 Stem cell research at academic centers ..... 147 Companies involved in stem cell technologies .................. 149 Concluding remarks about stem cells......... 153 Challenges and future prospects of stem cell research ..... 153 4. Clinical Applications of Cell Therapy ..... 155 Introduction 155 - 7 - Cell therapy for hematological disorders.... 155 Transplantation of autologous hematopoietic stem cells ........ 155 Hemophilias ...................... 155 Ex vivo cell/gene therapy of hemophilia B ......