Pluripotent Stem Cell Therapy for Diabetes

Preface
Contents
Contributors
Part I: Development and Differentiation of Beta Cells
	Mimicking Islet Development with Human Pluripotent Stem Cells
		1 Characteristics of Diabetes
		2 Beta Cell Replacement as a Cure for Type 1 Diabetes
		3 Deriving Functional Human Beta Cells In Vitro
		4 Key Events in Islet Development as a Blueprint for In Vitro Differentiation
		5 Applying Technologies for Cell Characterization and Perturbation
		6 Stem Cell Differentiation Recapitulates Islet Development
		7 A Piece Out of Place: The Puzzle of Enterochromaffin Cells
		8 Constructing an Islet from Stem Cells
		9 Extending Genetic Control of Islet Cell Fate
		10 Enhancing Stem Cell-Derived Islets
		References
	Genetic Regulatory Networks Guiding Islet Development
		1 Introduction
		2 GRN Facilitates Comprehension of the Regulatory Logic of Biological Processes
		3 Developmental Pathway of Pancreatic Lineages
		4 GRNs During Pancreas Organogenesis
			4.1 GRNs Controlling MP Generation
			4.2 GRNs for Tip Cell Specification
			4.3 GRNs Governing the EP Generation
			4.4 GRNs Governing Endocrine Lineage Specification
			4.5 GRNs Regulating Endocrine Maturation
		5 Conclusions and Perspectives
		References
	Pancreatic Cell Fate Specification: Insights Into Developmental Mechanisms and Their Application for Lineage Reprogramming
		1 Introduction
		2 Recent Insights Into Pancreas Development and Endocrine Fate Specification
			2.1 Pancreas Lineage Allocation and Specification
			2.2 Lessons Learned From Single-Cell Analyses: Resolving Developmental Paths
			2.3 Lessons Learned From Single-Cell Analyses: Building GRNs
		3 Direct Reprogramming for Pancreatic Cells
			3.1 Direct Lineage Reprogramming: Inside the Pancreas
			3.2 Direct Lineage Reprogramming: Outside the Pancreas
		4 Concluding Remarks and Future Directions
		References
	Factors Influencing In Vivo Specification and Function of Endocrine Cells Derived from Pancreatic Progenitors
		1 Introduction
		2 Pancreas Development in Mice and Humans
		3 The Role of Transcription Factors in Endocrine Cell Specification
		4 Regulation and Acquisition of Glucose-Stimulated Insulin Secretion
		5 Maturation of Human Embryonic Stem Cell-Derived β Cells In Vivo
		6 Conclusion
		References
	The Promises of Pancreatic Progenitor Proliferation and Differentiation
		1 Introduction
		2 Development of Pancreatic Progenitors
		3 hPSC-Derived Pancreatic Progenitor Proliferation
		4 Signaling Pathways Governing Pancreatic Progenitor Proliferation and Differentiation
		5 Conclusion
		References
Part II: Bioengineering
	Selecting Biocompatible Biomaterials for Stem Cell-Derived β-Cell Transplantation
		1 Clinical Islet Transplantation
		2 Strategies for Extrahepatic Transplantation
			2.1 The Immunoprotective Barrier Strategy
			2.2 The Revascularization Strategy
		3 Stem Cell-Derived β-Cells
		4 Biomaterials for Encapsulation of SCs
		5 Criteria That Influence Biocompatibility of Biomaterials
			5.1 Biomaterial Composition
			5.2 Porosity of Biomaterials
			5.3 Topography and Mechanical Properties
			5.4 Influence of Biomaterial Degradation
			5.5 Functionalization of Biomaterials
			5.6 Influence of Sterilization Techniques and Clean Fabrication
			5.7 Graft Monitoring
		6 Conclusions
		References
	Scaffolds for Encapsulation of Stem Cell-Derived β Cells
		1 Strategies for Extrahepatic Transplantation
		2 Nanoencapsulation
		3 Microencapsulation
			3.1 Extrahepatic Transplantation Sites for Microencapsulation Approaches
			3.2 Clinical Trials
		4 Macroencapsulation
			4.1 Extrahepatic Transplantation Sites for Macroencapsulation Approaches
		5 Macroencapsulation Devices
			5.1 Local Oxygen Delivery
				5.1.1 βAir
			5.2 Oxygen Generating Biomaterials
				5.2.1 OxySite
			5.3 Pre-vascularization or ‘Device-Less’ Strategies
			5.4 Membrane-Based Devices
				5.4.1 Theracyte Device
				5.4.2 Encellin Device
				5.4.3 MailPan Device
				5.4.4 Microwell-Array Device
			5.5 Intravascular Bioartificial Pancreas Devices (iBAPs)
			5.6 Fiber-Reinforced Hydrogels
			5.7 3D (Bio)printing Approaches
		6 What Do Patients Want Themselves?
		7 Concluding Remarks
		References
	Bioengineered Vascularized Insulin Producing Endocrine Tissues
		1 Shifting the Paradigm from In Vivo to Ex Vivo Islet Engraftment
		2 Reshaping the Architecture
			2.1 The ECM Relevance in Bioengineering the Vascularized Endocrine Pancreas
			2.2 Macroscale Scaffolds
			2.3 Microscale Scaffolds
			2.4 Nanoscale Scaffolds
		3 Reshaping the Vasculature
			3.1 The Relevance of the Pre-vascularization in Bioengineering the Vascularized Endocrine Pancreas
			3.2 Sources of Cells for the Generation of Vasculature Network
				3.2.1 Human Primary Endothelial Cells
				3.2.2 Human Endothelial Primary Progenitor Cells
				3.2.3 Pluripotent Stem Cells-Derived Endothelial Cells
		4 Reshaping the Endocrine Side: Alternative Sources and Their Application
		References
	3D Organoids of Mesenchymal Stromal and Pancreatic Islet Cells
		1 Background
			1.1 Type I Diabetes Mellitus
		2 Current Challenges and Progress in Cellular Therapeutics
			2.1 Islet and Pancreas Transplants
			2.2 Improvement of Islet Transplant Outcomes
			2.3 Scarcity of Suitable Islet Donors
			2.4 Immune Isolation of Islet Transplants
			2.5 Use of Novel, Prevascularized Organoids
			2.6 Induction of Immune Tolerance with Tregs
			2.7 Prevention of Teratoma/Teratocarcinoma Formation
			2.8 Islet Hormone Delivery, Extrahepatic Implantation Sites, and Retrievability
			2.9 Metabolic Control Achieved with Mono Hormonal (Insulin) Versus Polyhormonal (Insulin, Glucagon, SST, PPY, and Ghrelin) Cell Transplants
		3 Summary
		4 Technology: 3D Organoids of Mesenchymal Stromal and Pancreatic Islet Cells
			4.1 Rationale
			4.2 Hypothesis
		References
	Extracellular Matrix to Support Beta Cell Health and Function
		1 The Extracellular Matrix
		2 Pancreas and Islet ECM
			2.1 Comparing Whole Pancreas and Islet-Specific ECM
			2.2 ECM in Pancreas and Islet Development
			2.3 Differences in Islet ECM Across Species
			2.4 Roles of Specific ECM Proteins in Islet Health and Function
		3 Islet ECM Biomaterials
			3.1 Decellularization
			3.2 Non-Pancreas-Derived ECM-Based Scaffolds
			3.3 Non-ECM-Based Polymer Scaffolds
		4 Applications of ECM in Regenerative Medicine Therapies for Diabetes
		References
	Bioactive Materials for Use in Stem Cell Therapies for the Treatment of Type 1 Diabetes
		1 Immunoisolative Biomaterial Technologies for Type 1 Diabetes
			1.1 Classification of Immunoisolating Bioartificial Pancreas
			1.2 Immunoisolation Characterization
			1.3 Materials Used for Immunoisolation
		2 The Need for Bioactivity in Immuno-isolative Insulin Therapies
			2.1 Early Research and Successes
			2.2 Failures and limitations of Immunoisolation for IRT
			2.3 Classical Immunoisolation in the Clinic
		3 Part 2: Construction of Bioactive Systems for the Treatment of T1D
			3.1 Bioactive Materials for Oxygen Delivery and Supply
			3.2 Internal Systems
			3.3 Multi-material Scaffolds as Multimodal Bioactive Agents
			3.4 Oxygen Production
		4 Revascularization
		5 Insulin Production Maximization
		6 Reduction of Fibrotic Tissue Production
		7 Maintenance of Stem Cell Populations In Vivo
		8 Conclusion
		References
	Islet Macroencapsulation: Strategies to Boost Islet Graft Oxygenation
		1 Introduction
		2 Diffusion Is the Limiting Factor in a Macroencapsulation Setting
		3 Macroscale Device Design
		4 Cluster Size, Arrangement and Cell Source
			4.1 Significance of Homogenous and Small Cell Clusters
			4.2 Significance of Islet Arrangement: Microscale Device Design
			4.3 Significance of the Islet Source
		5 Oxygen Delivery Methods
			5.1 Oxygen-Generating Materials
			5.2 Applications in Islet Transplantation
		6 Material Selection
			6.1 The Immunoisolating Host-Graft Interface
			6.2 Islet Microenvironment
		7 Transplantation Site
		8 Perspectives
		Literature
Part III: Immunoescape
	Immunogenicity of Stem Cell Derived Beta Cells
		1 Introduction
		2 The Cause of Beta Cell Loss in T1D
		3 The Problems in Reversing Disease
		4 Reducing Immunogenicity of Stem Cell-Derived Beta Cells for Clinical Therapy
		5 Lessons from Stem Cells
		6 Lessons from Viruses
		7 Lessons from Cancer
		8 Lessons from T1D Immunopathogenesis and Immunotherapy
		9 Lessons from Clinical Islet Transplantation
		10 Future Perspectives
		References
	Immune Evasive Stem Cell Islets
		1 Mechanism of Rejection
		2 Invisible Cells
			2.1 HLA Matched Cells
			2.2 Abrogation of B2M
			2.3 Evasion of NK Cytotoxicity
			2.4 Tolerogenic Gene Expression
		3 Gene Editing of Isolated Islets
		References
	Islet Immunoengineering
		1 Introduction
		2 Immune Challenges Against Implanted Materials and Transplanted Islets
			2.1 The Instant Blood-Mediated Inflammatory Reaction
			2.2 The Foreign Body Response Against Implanted Materials
			2.3 Alloimmunity and Islet Transplant Rejection
		3 Biomaterial Properties and Modulation of the Immune Response
			3.1 Types of Biomaterials
			3.2 Global Features of Biomaterials
				3.2.1 Shape and Size
				3.2.2 Porosity
			3.3 Surface Properties of Biomaterials
				3.3.1 Surface Chemistry, Hydrophobicity, and Fouling
				3.3.2 Surface Topography
			3.4 Bulk Properties of Biomaterials
				3.4.1 Elasticity
				3.4.2 Molecular Weight
			3.5 Concluding Remarks
		4 Biomaterial Drug Delivery Strategies to Eliminate the Need for Chronic Systemic Immunosuppression After Islet Transplantation
			4.1 Drug Delivery via Biomaterials Improves Bioavailability and Stability
			4.2 Drug Delivery via Biomaterials Enables Islet Graft Targeting and Local Release
			4.3 Customization of Biomaterials to Further Enhance Targeted and Local Drug Delivery
			4.4 Concluding Remarks
		5 Approaches for Gene Editing of Stem Cell-Derived Islets
			5.1 Gene Editing via CRISPR-Cas9
			5.2 Human Leukocyte Antigen Knockout
			5.3 PD-L1 Expression
			5.4 Indoleamime-2,3-Dioxygenase Expression
		6 Islet Co-Transplantation with Immunomodulatory Cells
			6.1 Co-Transplantation with Mesenchymal Stem Cells
			6.2 Co-Transplantation with Regulatory T Cells
		References
Part IV: Preclinical Model and Translational Approaches
	Considerations Pertaining to Implant Sites for Cell-Based Insulin Replacement Therapies
		1 Introduction
		2 Type 1 Diabetes
			2.1 Autoimmunity After Islet Transplantation
		3 Islet Biology and Physiology
		4 Intraportal Islet Transplantation
		5 Physiology After Islet Transplantation
		6 Extrahepatic Pancreatic Islet Transplantation
			6.1 Intraperitoneal Space and Greater Omentum
			6.2 Spleen
			6.3 Kidney Capsule
			6.4 Subcutaneous Space
			6.5 Intramuscular Space
			6.6 Gastric Submucosa
			6.7 Bone Marrow
			6.8 Novel Extrahepatic Implantation Sites
		7 Special Considerations
			7.1 Stem Cell Replacement Therapies
			7.2 Approaches to Improve Islet Survival and Engraftment
		8 Conclusions and Final Recommendations
		References
	Genetic Safety Switches for Pluripotent Stem Cell-Derived Therapies for Diabetes
		1 Introduction
		2 Suicide Genes
			2.1 HSV-TK
			2.2 NTR
			2.3 Inducible Caspase 9
		3 Gene Promoters
			3.1 Ubiquitous Promoters
			3.2 Pluripotency Promoters
			3.3 Proliferative Cell Promoters
		4 Gene Delivery Approaches
			4.1 Random Integration
			4.2 Targeted Integration
		5 Escape
		6 Use of Suicide Gene Technology in Islet-Like Cell Products
		7 Conclusions
		References
	Safety Issues Related to Pluripotent Stem Cell-Based Therapies: Tumour Risk
		1 Introduction
		2 Recurrent (Epi)Genetic Aberrations in Human Pluripotent Stem Cells
			2.1 Highlighting the Most Recurrent Chromosomal Aberrations in hPSCs
			2.2 Recurrent Small Genetic Aberrations in hPSCs
			2.3 Epigenetic Aberrations in hPSCs
			2.4 The Effects of Different Reprogramming and Culture Techniques on hPSC (Epi)Genetic Integrity
		3 Techniques to Assess the Safety of Pluripotent Stem Cells for Regenerative Medicine
			3.1 Assessing Pluripotency and Malignancy: The Teratoma Assays and (Partial) Alternatives
			3.2 Additional Techniques to Assess and Modulate Pluripotency, Aberrant Pluripotent Cells and Undesired Cell Populations
			3.3 Interventional Techniques to Eliminate Off-Target Cell Populations
		4 Conclusion
		References
Part V: Beta Cell Replacement: Clinical Horizon
	An Ethical Perspective on the Social Value of Cell-Based Technologies in Type 1 Diabetes
		1 Introduction
		2 Existing Treatment Modalities
			2.1 Device-Based Treatment
			2.2 Transplantation
		3 Social Value of Stem Cell Technologies
			3.1 Beneficence
			3.2 Liberty and Autonomy
			3.3 Privacy
				3.3.1 Personal Data
				3.3.2 Visibility
				3.3.3 Alarms
			3.4 Justice
				3.4.1 Affordability
				3.4.2 Health Disparities
		4 Concluding Remarks
		References
	Beta Cell Replacement Cellular Products: Emerging Regulatory Perspectives and Considerations for Program Development
		1 Introduction
		2 Planning Overall Product Development: The Labeling Concept
		3 Which Product?
		4 Clinical Trials: From First-in-Human to Registration
			4.1 Clinical Trial Design
			4.2 Endpoints
		5 Expedited Programs: Fast Track, Regenerative Medicine Advanced Therapies (RMAT), Breakthrough, Accelerated Approval, Priority Review
		6 Conducting Trials During the COVID Pandemic
		7 Meetings with FDA
		8 Summary
		References
	Lessons Learned from Clinical Trials of Islet Transplantation
		1 Introduction: The Landmark Impact of the Edmonton Protocol
		2 Clinical Trials Utilizing the Edmonton Protocol
		3 The Edmonton Protocol in Islet-After-Kidney and Simultaneous Islet-Kidney Transplantation
		4 Adaptations of the Immunosuppressive Edmonton Protocol
		5 Sirolimus in Islet Transplantation: Friend or Foe?
		6 Immunosuppressive Regimens Including Co-stimulatory Blockade
		7 Protocols Including Engraftment-Enhancing Agents
		8 Islet Transplantation in Extra-Hepatic Sites
		9 Phase 3 Prospective Trials
		10 Long-Term Outcomes
		11 Impact of Islet Transplantation on Kidney Function
		12 Risks of HLA Sensitizitation
		13 What Are the Lessons Learned?
		References
	Minimal SC-β-Cell Properties for Transplantation in Diabetic Patients
		1 Introduction
		2 Insulin Secretion from β Cells
			2.1 Glucose Sensing and Metabolism
			2.2 Glycolytic Bottleneck in SC-β Cells
			2.3 Ca2+ Influx
			2.4 First-Phase and Second-Phase Insulin Secretion and Their Regulation
		3 Insulin Production and Processing
		4 β-Cell Maturation Genes
		5 SC-β Cells in Clinical Trials
		References
	Clinical Trials with Stem Cell-Derived Insulin-Producing Cells
		1 Introduction
		2 Rationale for the Need for Insulin-Producing Cells in Diabetes Therapy
		3 Rationale for the Need for a Stem Cell-Based Insulin-Producing Cell Therapy in Diabetes
		4 Mesenchymal Stem Cell-Based Clinical Trials in Diabetes Therapy
		5 Pluripotent Stem Cell-Based Clinical Trials in Diabetes Therapy
			5.1 ViaCyte Inc. Trials
			5.2 ViaCyte Inc. and CRISPR Therapeutics Collaboration Trials
			5.3 Vertex Pharmaceuticals Inc. Trial
			5.4 Other Developmental Trials
			5.5 Patient Selection-Key Inclusion and Exclusion Criteria
			5.6 Transplant Site
			5.7 Immunosuppression Protocols
		6 Preclinical Nonhuman Primate Pilot Studies
		7 Conclusions and Future Directions
			7.1 The Achievements of Stem Cell-Based Therapies for Diabetes
			7.2 A Debate of hESCs Versus hiPSCs
			7.3 Immune Protection
			7.4 Other Considerations
		References
	Modelling of Beta Cell Pathophysiology Using Stem Cell-Derived Islets
		1 Introduction
		2 Possibilities and Limitations of SC-Islets
		3 Monogenic Beta-Cell Defects
		4 Neonatal Diabetes Associated with Developmental Defects
		5 Neonatal Diabetes Associated with Beta-Cell Stress Mechanisms
		6 SC-Islet Models of Diabetes Presenting After the Neonatal Period (MODY)
		7 SC-Islet Models of Congenital Hyperinsulinism (CHI)
		8 In Vivo SC-Islet Models
		9 Functional Validation of Genetic Variants Associated with Polygenic Diabetes
		10 Conclusion
		References
Index