Cardiovascular Applications of Stem Cells

Foreword
Contents
About the Editor
1: Recent Advances in In Vitro Generation of Mature Cardiomyocytes
1.1 Introduction
1.2 Mature Cardiomyocyte Internal Complexity
1.3 CM Differentiation Protocols
1.3.1 Hormones
1.3.2 Energy Source
1.3.3 Prolonged Culture Period
1.3.4 Cellular Interactions
1.3.5 Biophysical Stimulation
1.3.6 Substrate Stiffness
1.3.7 Micropatterning
1.4 3D Culture System
1.5 Bioprinting
1.6 Microelectrode Cultured CM
1.7 Conclusion and Future Challenges
References
2: Cardiac Reprogramming with Stem Cells: An Advanced Therapeutic Strategy in Advanced Heart Failure
2.1 Introduction
2.2 Advanced Heart Failure: Definition and Contemporary Strategy
2.3 Modality of Action and Targets for Cell Care in Advanced HF
2.4 Cell Therapy in Advanced HF
2.4.1 Induced Pluripotent Stem Cells
2.4.2 Endothelial Progenitor Cells and Bone Marrow Mononuclear Cells
2.4.3 Cardiac Stem Cells
2.4.4 Mesenchymal Stem Cells
2.4.5 Skeletal Myoblasts
2.5 Future Directions for Investigations
2.6 Conclusion
References
3: Induced Pluripotent Stem Cells and Allogeneic Mesenchymal Stem Cell Therapy in Cardiovascular Diseases
3.1 Introduction
3.2 Allogeneic Cell Therapy
3.2.1 Moving Towards Allogeneic Cell Therapy
3.2.2 Cellular Recognition
3.2.3 Production Technology
3.2.4 Preclinical and Clinical Allogeneic Experience
3.2.4.1 Safety
3.2.4.2 Efficacy
3.2.4.3 Perspectives
3.3 Induced Pluripotent Stem Cells
3.3.1 iPSCs and Cardiomyocytes Maturation
3.3.2 iPSCs Maturation
3.3.3 Long QT Syndrome
3.3.4 Hypertrophic Cardiomyopathy and Dilated Cardiomyopathy
3.3.5 Brugada Syndrome
3.3.6 Familial Arrhythmogenic Right Ventricular Dysplasia
3.3.7 Biological Pacemakers
3.3.8 Status of iPSCs in the Treatment of Heart Failure
3.4 Administration Routes for Advanced Therapy Medicinal Products in Patients with Cardiovascular Diseases
3.4.1 Cell/ATMPs Currently Proposed Delivery Routes
3.4.1.1 Peripheral Intravenous Injections
3.4.1.2 Intracoronary Injections
3.4.1.3 Intramyocardial Injections
3.4.1.4 Transendocardial Approach
3.4.1.4.1 Electromechanically-Guided Procedure
3.4.1.4.2 Fluoroscopy-Guided Procedures
3.4.1.5 Transepicardial Approaches
3.4.1.5.1 Surgical Approach
3.4.1.5.2 Minimally Invasive Approach
3.4.1.5.3 Intrapericardial Approach
3.5 Conclusions
References
4: ``Heart Cells´´ Derived from Pluripotent Stem Cells and Therapeutic Applications
4.1 Introduction
4.2 Induced Pluripotent Stem Cell Sources
4.3 Cardiomyocytes
4.3.1 iPSC-Derived Cardiomyocyte Differentiation and Manufacturing Protocols
4.3.2 iPSC-Derived Cardiomyocyte Transplantation and Large Animal Studies
4.3.3 iPSC-Derived Cardiomyocyte Transplantation and Clinical Trials
4.4 Cardiac Progenitor Cells
4.4.1 iPSCs Cardiac Progenitor Cell Differentiation and Manufacturing Protocols
4.4.2 iPSC Cardiac Progenitor Cell Transplantation and Large Animal Studies
4.5 Cardiac Fibroblasts
4.6 Endothelial Cells
4.7 Conclusion
References
5: Stem Cells and Regenerative Medicine in Valvulopathies
5.1 Introduction
5.2 How a Valve Is Formed
5.3 Fetal and Adult Stem Cell and Valve Repair
5.4 Pluripotent Stem Cells as a Cell Source for Valve Regeneration in Valve Diseases Models
5.5 Perspectives
References
6: Rejuvenation and Regenerative Potential of Heart Stem Cells
6.1 Introduction
6.2 Research Progress of c-Kit+ Cardiac Stem Cells
6.2.1 Studies on c-Kit+ Cells from Bone Marrow
6.2.2 Studies on Endogenous Cardiac c-Kit+ Stem Cells
6.2.3 Role of C-Kit + Cardiac Stem Cells in Myocardial Repair
6.2.4 Limitations of C-Kit + CSCs in Myocardial Repair
6.3 Research Progress of Sca-1+ CSCs
6.4 Research Progress of Other Types of CSCs
6.4.1 Abcg2+ Side Population Cells
6.4.2 Isl1+ Cardiac Stem Cells
6.4.3 Bmi1+ CSCs
6.5 New Techniques to Investigate the Presence of Cardiac Stem Cells of Any Kind in the Heart
6.6 Summary and Future Prospect
References
7: Atrial Appendage-Derived Cardiac Micrografts: An Emerging Cellular Therapy for Heart Failure
7.1 Introduction
7.1.1 Cardiovascular Diseases
7.2 Cardiac Cell Therapy
7.3 Limitations of Advanced Approaches
7.3.1 Application Routes
7.3.2 Autologous Source Cardiac Tissue as a Cardiac Therapy
7.4 Clinically Straightforward Therapies
7.5 The Atrial Appendages as an Autologous Source for Cells and Factors to Activate the Epicardium
7.5.1 Autologous Atrial Appendage Micrografts
7.6 Application of Atrial Appendage Cells for Therapeutic Purposes
7.7 Surgical Use of Atrial Appendage and Atrial Appendage Micrografting
7.7.1 Clinical Results on Epicardial Transplantation of Atrial Appendage Micrografts
7.7.2 Atrial Appendage Micrografts and Gene Therapy
References
8: Cardiac Progenitor Cells in Cardiac Tissue Repair
8.1 Introduction
8.2 Cardiac Progenitor Cell Populations
8.3 Mechanisms of Action of CPCs in Cardiac Repair
8.4 Cardiac Progenitor Cell-based Clinical Trials
8.5 Methods of CPCs Harvesting and Delivery
8.6 Limitations and Disadvantages of CPCs
8.7 Conclusions
References
9: Cardiac Tissue Regeneration Based on Stem Cell Therapy
9.1 Introduction
9.2 Stem Cell Therapy for Cardiac Regeneration
9.2.1 Stem Cell Types for Cardiac Tissue Regeneration
9.2.2 Stem Cell Differentiation
9.3 Stem Cell Therapy Strategies for Cardiac Tissue Regeneration
9.3.1 Direct Injection of Stem Cells into the Infarct Area
9.3.2 Hydrogels in Cardiac Stem Cell Regeneration
9.3.2.1 Hydrogels Based on Natural Polymers
9.3.2.2 Hydrogels Based on Synthetic Polymers
9.3.2.3 Injectable Decellularized Tissues
9.4 Scaffolds in Cardiac Stem Cell Regeneration
9.5 Nanotechnology in Cell Therapy-based Cardiac Regeneration
9.6 Conclusion
References
10: Stem Cell Applications in Cardiac Tissue Regeneration
10.1 Introduction
10.1.1 Cardiomyocyte Maturation
10.1.2 Cell Regeneration
10.2 Stem Cells
10.2.1 ESCs and iPSCs
10.2.2 Adult Stem Cells
10.3 Transdifferentiation
10.4 Driving Cells to a Cardiac Fate
10.4.1 Key Transcription Factors Regulate Cardiac Differentiation
10.4.2 Regulation of Cardiac Differentiation by Growth Factors
10.4.3 Modulation of MicroRNAs
10.4.4 Small Molecule Compounds
10.4.5 Bioengineering Scaffolds
10.5 Perspectives
References
11: Therapeutic Targeting of Epicardial and Cardiac Progenitors in the Heart Regeneration
11.1 Introduction
11.1.1 Epicardium and Cardiac Regeneration
11.2 The Epicardium as a Therapeutic Hub for Cardiac Renewal
11.3 Resident Cardiac Progenitors
11.4 Epicardium as Hypoxic Cardiac Niche
11.5 Therapeutic Targeting of the Epicardium in the Cardiac Regeneration
11.6 Future Prospective
References
12: Human Myoblast Genome Therapy and the Regenerative Heart
12.1 Introduction
12.1.1 Myocardial Cell Degeneration
12.1.2 Spontaneous Myocardial Regeneration
12.2 Gene Therapy
12.2.1 Gene Regulation and Expression
12.2.2 Nature´s Chest of Gene Medicine
12.2.3 Skeletal Muscle Regeneration Using Myoblasts
12.3 Human Genome Therapy
12.3.1 Myoblast Transfer Therapy (MTT)
12.3.2 MTT: A Genetic Cell Therapy that Pioneered Regenerative Medicine
12.3.3 MTT Safety and Efficacy Were Historically Established in FDA-Approved DMD Studies
12.4 Heart Muscle Regeneration
12.4.1 Preclinical Heart Cell Therapy (HCT)
12.4.2 World´s First Human Myoblast Transfer into the Heart
12.4.3 Proof-of-Concept and Mechanisms
12.4.4 Evidence for Natural Cell Fusion
12.5 Autograft Versus Allograft
12.5.1 MHC-1 Antigens on Cultured Human Myoblasts
12.5.2 Two-Week Versus Life-Long Immunosuppression
12.6 Severe Myocardial Infarction
12.7 Early Clinical HCT
12.7.1 Myoblast Autograft
12.7.2 Myoblast Allograft
12.8 Myoblasts Hijacked by Cardiac Stem Cells
12.9 Allogeneic Myoblast Transplantation (AMT) Is Safe and Efficacious in Treating End-Stage HF Subjects
12.9.1 Regulatory
12.9.2 Case Selection
12.9.3 Methods
12.9.3.1 Manufacture of Allogeneic Human Myoblasts
12.9.3.2 Muscle Biopsy
12.9.3.3 Myoblast Preparation
12.9.3.4 Cyclosporine Immunosuppression
12.9.3.5 Clinical Research Procedure
12.9.3.6 AMT
12.10 Results
12.10.1 Statistical Analyses
12.10.2 Safety Assessment: Adverse Reaction Assessment
12.10.3 Efficacy Assessment: Objective Evaluation
12.10.3.1 Subjective Evaluation
12.11 Discussion
12.12 Perspectives
12.13 Conclusion
12.14 Angiomyogenesis
12.15 Autonomous Robotic Cell Injection Catheter System
12.16 Stimulation Therapies and Fractal Dynamics to Complement HCT Treatment
12.17 Heart Cell Therapy (HCT) Patents of Professor Peter K. Law
12.18 FDA, EMA-Approved MTT INDs for HCT
12.19 Conclusion
References
13: The Effect of Time of Cell Delivery on Post-MI Cardiac Regeneration: A Review of Preclinical and Clinical Studies
13.1 Introduction
13.2 Cell-Based Therapy
13.3 Small Experimental Animal Studies
13.3.1 Experimental Mouse Heart Model
13.3.2 Experimental Rat Heart Model Studies
13.4 Large Experimental Animal Studies
13.4.1 Rabbit Heart Model
13.4.2 Experimental Porcine Heart Model
13.5 Clinical Studies
13.6 Conclusions and Future Perspective
References
14: Avant-Garde Hydrogels as Stem Cell Niche for Cardiovascular Regenerative Medicine
14.1 Introduction
14.2 A Brief Glimpse at the Current Treatment Modalities
14.3 Recent Advances in Hydrogels for Cardiac Remodeling
14.4 Making Heart from Heart
14.5 Target-Based Functioning Hydrogels for Cardiac Regeneration
14.5.1 Angiogenic Hydrogels for De Novo Vascularization
14.5.2 Immunomodulatory Hydrogels
14.5.3 Hydrogels for Matrix Metalloproteinase Inhibition
14.5.4 ROS Cleansing and Oxygen Generating Hydrogels
14.5.5 Conductive Hydrogels
14.6 Conclusion and Future Outlook
References
15: Human Stem Cell-Derived Cardiac Organoid-Like Structures: Generation and Applications
15.1 Introduction
15.2 The Myocardium
15.3 Generation of Human Cardiac 3D-Engineered Microtissues
15.3.1 Roadmap of Cardiogenic Differentiation from PSCs
15.3.2 Generation of Spheroids and Cardiac Organoids by Self-Assembling
15.3.3 Generation of Cardiac Organoids and EHTs by Directed Assembly: The Playground of Biotechnology
15.3.3.1 Engineered Heart Tissues (EHT) and Substrates
15.3.3.2 Maturation Strategies
15.3.4 Microtissues and 3D Printing
15.4 Application of Human Cardiac Organoids
15.4.1 Examples of Cardiac Disease Modeled with Human Cardiac Organoids
15.4.1.1 Heart Failure
15.4.1.2 Myocardial Infarction (MI)
15.4.1.3 Cardiomyopathies and Genetic Disorders
15.4.2 Drug Screening
15.4.2.1 Drug Toxicity
15.4.2.2 Drug Development
15.5 Cardiac Development
15.6 Cell Therapy and Regenerative Therapy
15.7 Cardiac Organoids and Macrophages
15.8 Future Developments and Conclusion
References
16: Cardiovascular Stem Cell Applications in Experimental Animal Models
16.1 Introduction
16.1.1 Overview of Stem Cell Therapy in Cardiovascular Disorders
16.2 Stem Cell Therapy for Dilated Cardiomyopathy
16.3 Reprogrammed Somatic Cells (Induced Pluripotent Stem Cells)
16.4 Stem Cell Therapy for Myocardial Infarction
16.5 Conclusions
References
17: Stem Cells in Heart Failure: Future Perspective
17.1 Heart Failure with Reduced Ejection Fraction
17.1.1 Background
17.1.2 Targets of Reparative Medicine in Heart Failure Patients
17.1.3 Advanced Therapy Medicinal Products for Heart Failure
17.1.4 Phase II-III Randomized Clinical Trials
17.1.5 Future Directions
17.2 Heart Failure with Preserved Ejection Fraction
17.2.1 Background
17.2.2 Potential Targets for Cell Therapy in HFpEF
17.2.3 Potential Effects of Cell-Based Therapy in HFpEF
17.2.4 Preclinical Evidence of Cell Therapy Effects in HFpEF
17.2.5 Clinical Evidence of Cell Therapy Effects in HFpEF
17.2.6 Factors Affecting the Clinical Outcome
17.2.7 Cell Type and Properties
17.2.7.1 Dosage
17.2.7.2 Methods of Administration
17.2.7.3 Immunogenicity
17.2.7.4 Preconditioning
17.2.7.5 Biomaterials
17.2.7.6 Optimal Administration Time
17.2.7.7 Safety Issues
17.2.7.7.1 Tumorigenesis
17.2.7.7.2 Arrhythmias
17.2.7.7.3 Tracking and Targeting SCs
17.2.7.8 Mechanism of Action
17.3 Conclusion
References