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Functional Neural Transplantation IV: Translation to Clinical Application, Part B

Copyright

Contributors

Contents

Preface

Chapter 1: Stem cell transplantation for spinal cord injury repair

1. Introduction

2. MSCs for SCI Repair

2.1. Sources of MSCs

2.2. Mechanism of MSC Transplant for SCI Repair

2.3. Neuronal Differentiation Potential of MSCs

2.4. Clinical Trials of MSCs for SCI

3. NSCs for SCI Repair

3.1. Sources of NSCs and Their Differentiation Potential

3.1.1. NSCs from embryonic/fetal CNS tissue

3.1.2. NSCs from adult CNS tissue

3.1.3. NSCs from ES cells

3.1.4. NSCs from iPSCs

3.1.5. Direct reprogramming of somatic cells into neurons or NSCs

3.2. NSCs or NPCs for Neural Protection and Remyelination

3.3. Axonal Growth and Connectivity From NSC Graft

3.4. Host Axonal Regeneration and Connectivity With NSC Grafts

3.5. Functional Outcomes

4. Future Perspective

Acknowledgments

References

Chapter 2: Plasticity and regeneration in the injured spinal cord after cell transplantation therapy

1. Introduction

2. Optimal Timing of Cell Transplantation and Plasticity After SCI

3. Cell Transplantation for Neural Regeneration and Plasticity

3.1. Neural Stem/Progenitor Cells

3.2. Embryonic Stem Cell-Derived Neural Stem Cells

3.3. iPSC-Derived NSPCs

3.4. Mesenchymal Stromal Cells

3.5. Olfactory Ensheathing Cells

3.6. Schwann Cells

4. Plasticity and Regeneration After Cell Transplantation Therapy

4.1. Remyelination

4.2. Reconstruction of Neural Circuits

4.3. Neurotrophic Support

5. Conclusions

Acknowledgments

References

Chapter 3: Transplantation of GABAergic interneurons for cell-based therapy

1. Introduction

2. Development of Telencephalic GABAergic Interneurons

2.1. Tangential Migration

2.2. Origins and Diversity

3. Transplantation and the Study of Brain Development

3.1. Interneuron Intrinsic Developmental Program

3.2. Interneuron Fate and Survival

4. Transplantation and Cortical Plasticity

5. Disease-modifying Properties of MGE Transplants

5.1. Schizophrenia

5.2. Epilepsy

5.3. Parkinson's Disease

5.4. Alzheimer's Disease

5.5. Neuropathic Pain

6. Conclusion

Acknowledgments

References

Chapter 4: Rebuilding CNS inhibitory circuits to control chronic neuropathic pain and itch

1. Introduction

2. Medial Ganglionic Eminence-Derived Inhibitory Interneurons

3. MGE Cell Transplants to Treat Neuropathic Pain

3.1. MGE Cells Ameliorate Neuropathic Pain

3.2. MGE Cells Integrate Extensively Into Host Spinal Cord Circuitry

3.3. Functional and Anatomical Evidence for Synaptic Connectivity of Transplanted MGE Cells

3.4. Is There an Endogenous GABAstat That Regulates MGE-Derived Inhibitory Control?

3.5. MGE Cells Prevent the Development of Mechanical Allodynia

4. Cell Transplants for the Management of Chronic Itch

4.1. MGE Cells Reduce Spontaneous Scratching and Resolve Skin Lesions in Bhlhb5 Mutant Mice

4.2. MGE Transplants Are Also Effective Against Chronic, Inflammatory Itch

5. Translating Preclinical Transplantation Studies to the Clinic

6. Conclusions

References

Chapter 5: From transplanting Schwann cells in experimental rat spinal cord injury to their transplantation into human in ...

1. Introduction

2. Advantages of Primary SCs for Cell Therapy in SCI

3. SC Proliferation: Cues for Achieving Expansion by Using Heregulin and cAMP-Stimulating Agents

4. Other Sources of SCs

5. SC Transplantation Studies in Rat SCI Models

6. Development of the Clinically Relevant Protocol for Manufacturing Autologous Human SCs

6.1. Making SCs Proliferate in Culture

6.2. The Brockes Protocol: Fibroblast Depletion to Purify SC Cultures

6.3. The Porter Protocol: Elimination of Cholera Toxin and Modification of the Culture Substratum

6.4. Transformation of SCs With Extended Passages

6.5. The Challenge of Isolating SCs From Adult Rat Nerve

6.6. The Morrissey-Kleitman Protocol: Increasing Adult SC Expansion by Using Multiple Replating of Nerve Explants and Del ...

6.7. The Morrissey-Kleitman-Levi Protocol: Replacement of GGF with Recombinant Heregulin and Addition of Cholera Toxin Ba ...

6.8. The Casella Protocol: Delayed Dissociation, Culture on Laminin, and Elimination of Cholera Toxin

6.9. The Athauda Protocol: Manufacture of a Clinical Grade Human SC Product

7. Clinical Research for Spinal Cord Injury

7.1. Preclinical Studies to Gain FDA Approval for a SC Trial

7.2. Regulatory Requirements to Manufacture SCs for Trials

7.3. The First SC Clinical Trial at the Miami Project

7.4. SC Processing and Transport to the Transplantation Site

7.5. Trial Outcomes

7.6. The Next Trial

7.7. Next Steps in SC Manufacture and Quality Assurance

8. Conclusion

Acknowledgments

References

Chapter 6: Recruitment of endogenous CNS stem cells for regeneration in demyelinating disease

1. Introduction

2. Overview: Myelination and Remyelination

2.1. The Myelinated CNS: An Evolutionary Milestone

2.2. Developmental Myelination

2.3. The OPC

2.4. Remyelination: The Default Response to a Demyelinating Insult

3. Demyelination

3.1. Myelin Disorders

3.2. Consequences of Demyelination

3.3. Acquired Demyelinating Disorders

3.4. Experimental Models of Demyelination

4. Failure of Remyelination

4.1. Why Does Remyelination Fail?

4.2. At What Stage Does Remyelination Fail?

4.3. Remyelination Failure: Intrinsic Properties of Remyelinating Cells vs Extrinsic Properties of the Environment

4.3.1. Dysregulation of the innate immune response

4.3.2. Dysregulation of the migratory cues

4.3.3. Inhibitory extracellular matrix molecules within the lesion

4.3.4. Axon-oligodendrocyte interactions

4.4. Efficient Remyelination: The Role of Cell Signaling Pathways

5. Enhancing Endogenous Stem Cells: Current and Future Therapies

5.1. Rejuvenation as an Approach to Enhance Remyelination

5.2. The Translational Pathway: From Bench to Bedside

5.2.1. Lingo1 inhibition

5.2.2. RXR agonists

5.3. Drug Repurposing for Remyelination

5.4. Autoantibodies: The Solution From Within

6. Concluding Remarks

Acknowledgments

References

Chapter 7: Progenitor cell-based treatment of glial disease

1. Introduction

2. GPCs In Vivo

3. Identifying Optimal Donor Cell Phenotypes for Treating Myelin Disorders

4. Pediatric Myelin Disorders as Targets of Progenitor cell-based Therapy

4.1. Metabolic and Storage Disorders of Myelin

4.2. Disorders of Myelin Formation and Maintenance

4.3. The Dilemma of Disease-Specific Dosing

5. Adult Disease Targets of GPC-based Treatment

5.1. Progenitor Cell Therapy for Multiple Sclerosis

5.2. Progenitor Cell Therapy for Adult Structural Demyelinations

5.3. Remyelination of Spinal Lesions

6. Human Glial Chimeric Mice Reveal Human-Selective Aspects of Both Glial Function and Dysfunction

7. Glial Transplant-Mediated Amelioration of Neurodegenerative Disorders

8. Human Glial Involvement in—and Potential Rescue of—the Neuropsychiatric Disorders

9. Conclusions

Acknowledgments

References

Chapter 8: Pluripotent stem cells and their utility in treating photoreceptor degenerations

1. Introduction

2. Retinal Degeneration

3. Therapeutic Avenues for Retinal Diseases

3.1. Immunotherapy

3.2. Gene Therapy

3.3. Electronic Retinal Prosthesis

3.4. Repair by Cell Transplantation

3.4.1. Transplantation of donor-derived single cell photoreceptor suspensions

3.4.2. Cytoplasmic material transfer

3.4.3. Transplantation of donor-derived photoreceptors into severely degenerated retinae

3.4.4. Transplantation of retinal sheets

4. Pluripotent Stem Cells

4.1. Pioneering Work in Neural Specification and Retinal Differentiation

4.2. Growing Retinal Organoids Derived From PSCs

5. Challenges for PSC Research

6. Clinical Prospects

6.1. Cell Transplantation

6.2. Disease Modeling

6.3. Drug Screening/Evaluation of Potential Treatments

7. Conclusion

Acknowledgments

References

Chapter 9: Stem cell-derived retinal pigment epithelium transplantation for treatment of retinal disease

1. Age-Related Macular Degeneration

2. RPE, Its Functions, and Role in AMD

3. Proof-of-Principle Studies

4. Clinical Results and Considerations

5. Production of Cell Therapies for AMD

5.1. Regulations

5.2. Preclinical Considerations

5.3. Manufacturing

6. Future

Acknowledgments

References

Chapter 10: Transplantation of reprogrammed neurons for improved recovery after stroke

1. Introduction

2. Improving Functional Recovery in Stroke by Transplantation of Reprogrammed Neurons

3. Evidence for Reconstruction of Neuronal Circuitry After Implantation of Reprogrammed Cells in Stroke-Injured Brain

4. Direct in vitro and in vivo Reprogramming of Somatic Cells to Neurons

5. Research Challenges and Prospects for Clinical Translation

6. Conclusions

Acknowledgments

References

Combined Index

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