Progenitor Cell Therapy for Neurological Injury (eBook)

Preface 6
Contents 8
Contributors 10
Chapter 1: Basics of Stem and Progenitor Cells 12
1.1 Speaking the “Stem Cell Language”: Definitions and Criteria 13
1.2 Adult Stem Cells 14
1.2.1 Bone Marrow-Derived Cell Populations 15
1.2.1.1 Mesenchymal Stromal Cells 15
1.2.1.2 Multipotent Adult Progenitor Cells 16
1.2.1.3 Hematopoietic Stem Cells 16
1.2.1.4 Mononuclear Cells 17
1.2.2 Nervous System-Derived Cell Populations 17
1.2.2.1 Neural Stem Cells 17
1.2.3 Other Niche-Derived Adult Stem Cell Populations 19
1.2.3.1 Umbilical Cord Blood and Umbilical Cord Matrix Stroma Stem/Progenitor Cells 19
1.2.3.2 Embryonic Stem Cells 19
1.3 Nuclear Reprogramming 20
1.3.1 Induced Pluripotent Stem Cells 21
1.3.2 Somatic Cell Nuclear Transfer, Cellular Fusion, and Exposure to Cellular Extract 21
1.4 Interaction Between the Cell and the Immune System 22
1.5 The Age of the Isolated Cell 23
1.6 The Importance of Critical Examination of the Stem/Progenitor Cell Population and Concluding Remarks 25
References 25
Chapter 2: Progenitor Cell Tissue Engineering 30
2.1 Introduction 31
2.2 Tissue Scaffold Goals 32
2.2.1 High Surface Area-to-Volume Ratio 33
2.2.2 Suitable Microenvironment 33
2.2.3 Appropriate Biomaterial 35
2.2.4 Brain-Specific Considerations 36
2.3 Fabrication of Tissue Scaffolds 37
2.3.1 Thermally Induced Phase Separation 38
2.3.1.1 Solid–Liquid Phase Separation 38
2.3.1.2 Liquid–Liquid Phase Separation 39
2.3.2 Leaching 40
2.3.3 Electrospinning 40
2.3.3.1 System Overview 40
2.3.3.2 Process Conditions 42
Electric Field 43
Field Strength 43
Field Shape 43
Structure 43
Solution Flow Rate 44
2.3.3.3 Material Solution Properties 44
Polymer Selection 44
Molecular Weight 44
Solvent Selection 45
Solution Concentration 45
2.3.3.4 Central Nervous System-Based Applications 45
2.3.4 Rapid Prototyping 47
2.3.4.1 Selective Laser Sintering 48
2.3.4.2 3D Printing/Inkjet Deposition 49
2.3.4.3 BioPlotting/Fused Deposition Modeling 50
2.3.4.4 Stereolithography 51
2.4 Conclusion 52
References 53
Chapter 3: Stem Cell Delivery Methods and Routes 58
3.1 Current Delivery Vehicles 59
3.1.1 Intravenous Infusion 59
3.1.2 Intra-arterial Infusion 66
3.1.3 Direct Implantation 69
3.1.4 Intrathecal Injection 70
3.2 Novel Delivery Methods/Vehicles 71
3.2.1 Scaffold Constructs 71
3.2.2 Hydrogels 72
3.2.3 Enhancement of Progenitor Engraftment 73
3.2.3.1 Effects of Age/Number of Cells Infused 73
3.2.3.2 Homing Receptors 73
3.2.3.3 Hypoxia 73
3.2.3.4 Toll-Like Receptors 74
3.3 Barriers to Cell Therapy: Effect of Catheter Infusion 74
3.4 Future Considerations 75
References 76
Chapter 4: Neural Progenitor Cells for Traumatic Brain and Spinal Cord Injury: Endogenous Cell Rescue Versus Replacement Mechanisms 80
4.1 Introduction 81
4.2 Central Nervous System Cell Types or Relationships to Injury and Progenitor Cell Therapy 81
4.2.1 Astrocytes 81
4.2.2 Oligodendrocytes 82
4.2.3 Microglia 82
4.2.4 Endothelial Cells and Pericytes 84
4.2.5 Neural Progenitor Cells 84
4.3 Traumatic Brain Injury: Effects on Endogenous and Transplanted Neural Stem Cells 87
4.3.1 Endogenous Neural Stem Cells 87
4.3.2 Transplanted Neural Stem Cells 88
4.4 Spinal Cord Injury: Effects of Endogenousand Transplanted Neural Stem Cells 91
4.4.1 Endogenous Neural Stem Cells 91
4.4.1.1 Modulation of Cytokines/Growth Factors: Potential Approach to Modify Injury Response/Progenitor Cell Proliferation 92
4.4.1.2 Growth Factor/Genetic Manipulation 92
4.4.1.3 Other Mechanisms 93
4.4.2 Neural Stem Cell Transplantation 93
4.4.2.1 Timeline for Transplantation 94
4.4.2.2 Embryonic/Fetal-Derived Neural Stem Cells 94
4.4.2.3 Adult Neural Stem Cells 98
4.5 Discussion 101
References 101
Chapter 5: Traumatic Brain Injury Pathophysiology/Models 107
5.1 Traumatic Brain Injury Classification 108
5.2 Traumatic Brain Injury Pathophysiology:Implications for Future Targets 110
5.2.1 Post-injury Neural Excitotoxicity 111
5.2.2 Cerebral Edema 112
5.2.3 Mitochondrial Injury 113
5.2.4 Neuronal Inflammation 113
5.3 In Vivo Models 115
5.3.1 Direct Impact Injury 116
5.3.1.1 Fluid Percussion Injury 116
5.3.1.2 Controlled Cortical Impact Injury 117
5.3.1.3 Focal Cortical Compression 120
5.3.2 Non-impact Acceleration Injury 121
5.3.3 Blast-Induced Neurotrauma 121
5.4 Cell Therapy 122
5.4.1 Clinical Significance 122
5.4.2 Possible Therapeutic Mechanisms 123
5.4.3 Barriers to Treatment 125
5.4.3.1 Effect of Elevated Serum Osmolarities 125
5.4.3.2 Emboli and Tumor Development 126
5.5 Future Considerations 127
References 127
Chapter 6: Traumatic Brain Injury: Relationshipof Clinical Injury to Progenitor Cell Therapeutics 133
6.1 Introduction 134
6.1.1 Adult Versus Pediatric TBI: Pathophysiological Differences 137
6.1.2 Epidural Hematomas 138
6.1.3 Subdural Hematomas 138
6.1.4 Edema/Shearing 138
6.2 Pathophysiology as Linked to Progenitor Cells 139
6.3 Applications of Preclinical Data 140
6.3.1 Potential Mechanisms of Action for Adult Progenitor Cell Treatment of Traumatic Brain Injury: Bone Marrow Mononuclear Cell, Mesenchymal Stromal Cell, Multipotent Adult Progenitor Cell, Human Umbilical Cord Blood, and Derivatives 140
6.4 Outcomes Measures 142
6.4.1 Functional 142
6.4.2 Structural Correlates to Functional Outcome Measures 143
6.4.2.1 Initial Imaging 143
6.4.2.2 Options for Structural Analyses 145
6.5 Regulatory Aspects/Logistical Considerations of Progenitor Cell Therapy for TBI 146
6.5.1 Regulatory Issues 146
6.5.2 Informed Consent 149
6.5.3 Language 149
6.5.4 Coordination 149
6.5.5 Infrastructure Requirements 149
6.6 Current and Future Studies 150
References 151
Chapter 7: Cell-Based Therapy for Stroke 153
7.1 Introduction 154
7.2 Cell Types and Sources 155
7.2.1 Neural Stem Cells 155
7.2.1.1 Human Embryonic Stem Cell-Derived Neural Stem Cells 155
7.2.1.2 Human Fetal-Derived Neural Stem Cells 155
7.2.1.3 Cell Lines 155
7.2.2 Non-neural Stem Cells 156
7.2.2.1 Adipose Tissue Mesenchymal Progenitor Cells 156
7.2.2.2 Bone Marrow Mesenchymal Stem Cells 156
7.2.2.3 Umbilical Cord Blood Cells 157
7.2.2.4 Bone Marrow-Derived Mononuclear Cells 157
7.2.2.5 Peripheral Blood Progenitor Cells and Peripherally Derived Mononuclear Cells 157
7.3 Possible Mechanisms of Cellular Therapy 157
7.4 Key Translational Barriers to AdministeringCells as a Therapy for Stroke 159
7.4.1 Cell Tracking and Imaging 159
7.5 Potential Risks of Stem Cell Therapy 160
7.6 Routes of Stem Cell Delivery 160
7.6.1 Intracerebral Delivery 160
7.6.2 Intracerebroventricular/Intracisternal Delivery 161
7.6.3 Intravenous Delivery 161
7.6.4 Intra-arterial Delivery 162
7.7 Dose of Stem Cells 162
7.8 Timing of Stem Cell Delivery 163
7.9 Clinical Trials 163
7.10 STEPS Guidelines 165
References 165
Chapter 8: Spinal Cord Injury Pathophysiology and Progenitor Cell Therapy 172
8.1 Introduction 173
8.2 Economics 174
8.3 Pediatric Versus Adult Spinal Cord Injury 174
8.3.1 Biomechanical Considerations 174
8.3.2 Age and Injury Pattern 176
8.3.3 Outcome 177
8.4 Biochemical and Cellular Sequela of Spinal Cord Injury 177
8.5 Immune System Response to Spinal Cord Injury 178
8.6 Intrinsic Spinal Cord Repair Potential 180
8.7 Preclinical Spinal Cord Injury Progenitor Cell Experience 180
8.7.1 Replace Missing Myelin-Forming Cells 180
8.7.2 Replace Missing Neurons 181
8.7.3 Support Endogenous Spinal Cord Repair 181
8.7.4 Modulate Immune Response to Enhance Repair 181
8.7.5 Biomatrix Studies 182
8.7.6 Experimentally Induced Allodynia 182
8.8 Human Spinal Cord Injury Stem Cell Trials 183
8.8.1 Human Trials Using Autologous Bone Marrow-Derived Mononuclear Cells Delivered by Intravenous or Intra-arterial Infusion 183
8.8.2 Human Trials Using Autologous Bone Marrow-Derived Mononuclear Cells Delivered by Lumbar Puncture 184
8.8.3 Human Trials Using Bone Marrow-Derived Mononuclear Cells Delivered by Direct Injection or Surgical Implantation into the Injured Spinal Cord 185
8.8.4 Human Trials Using Embryonically Derived Stem Cell Products 185
8.9 Conclusion 186
References 186
Chapter 9: Progenitor Cell Therapy for the Treatment of Central Nervous System Injury: A Review of the State of Current Clinical Trials 190
9.1 Ischemic Stroke 191
9.2 Traumatic Brain Injury 195
9.3 Spinal Cord Injury 196
9.3.1 Human Trials Using Autologous Bone Marrow Mononuclear Cells Delivered by Intravenous or Intra-arterial Infusion 196
9.3.2 Human Trials Using Autologous Bone Marrow Mononuclear Cells Delivered by Lumbar Puncture 197
9.3.3 Human Trials Using Bone Marrow Mononuclear Cells Delivered by Direct Injection or Surgical Implantation into the Injured Spinal Cord 198
9.3.4 Human Trials Using Embryonically Derived Stem Cell Products 198
9.4 Conclusions 199
References 200
Index 201