Handbook of Stem Cell Therapy

Foreword
Contents
About the Editor
Section Editors
Contributors
Part I: Cell-Based Therapy Approach: Mesenchymal Stem Cell-Based Therapy
1 Human Mesenchymal Stem Cells: The Art to Use Them in the Treatment of Previously Untreatable
Introduction
Mesenchymal Stem Cells Current Status: The ``Problems´´ That in Reality Do Not Exist
Practical Approaches: The Golden Standards, i.e., ``Good Biological Praxis´´ (GBP) Using the Historical Laboratory Experience
Data Extrapolation from Small Animal Studies to Humans Is Unfounded and Without Relevance
Current Research Paradigm: MSCs in Advanced Phases of Clinical Trials Although Understandable Is Far from Personalized Medicine
A Case of Autologous Versus Allogeneic MSCs, an Unanswered Question
A Case for Autologous Cells
Autologous Cells from Patients Are Also ``sick´´
Autologous Cells in Elderly Patients Are Also Aged
A Case for Allogeneic Cells
Logistic Advantage of Allogenic MSCs
Allogenic MSCs Overcome the Limitations of Aging and Sickness of Autologous Cells
Quality Control of MSCs Preparation: A Prerequisite for Optimal Prognosis
Conclusion
References
2 Sources and Therapeutic Strategies of Mesenchymal Stem Cells in Regenerative Medicine
Introduction
Mesenchymal Stem Cells
Sources of Mesenchymal Stem Cells
Bone Marrow-Derived MSCs
Advantages of BM-Derived MSCs
Limitations of BM-Derived MSCs
Adipose Tissue-Derived MSCs
Advantages of Adipose Tissue-Derived MSCs
Limitations of Adipose Tissue-Derived MSCs
Isolation of Adipose Tissue-Derived MSCs
Clinical Applications of Adipose Tissue-Derived MSCs
Umbilical Cord-Derived MSCs
Human Umbilical Cord Structure and Function
Advantages of WJ-Derived MSCs
Limitations of WJ-Derived MSCs
Isolation Methods of WJ-Derived MSCs
Clinical Applications of WJ-Derived MSCs
Therapeutic Strategies of Using MSCs
Tissue Regeneration
Immunomodulation of MSCs
Extracellular Vesicles/Exosomes Derived from MSCs
MSCs Act as an Efficient Tool for Gene Therapy
References
3 Considerations for Clinical Use of Mesenchymal Stromal Cells
Introduction
Biological Characteristics
Phenotypic Profile
MSCs´ Proliferation
Differentiation Capacity
Cellular Transformation
Mechanism of Action
Cell Migration Toward Damaged Tissues
Tissue Repair
Immunomodulatory Potential
Preclinical Applications
MSC-Based Therapy for Autoimmune Diseases
MSCs for Cancer Treatment
The Anti-tumor Activity of MSCs
The Pro-tumor Activity of MSCs
The Imprint of Disease on MSCs
Considerations for Clinical Applications
Safety Concerns
Cell Manufacturing for Clinical Use
Considerations for Cellular Medicament
General Considerations
Attempts to Improve the Therapeutic Outcomes of Cellular Medicament
Concluding Remarks and Future Perspective
Cross-References
References
4 Stem Cells in Wound Healing and Scarring
Introduction
Wound-Healing Process
Normal Wound Healing
Impaired Wound Healing
Excessive Wound Healing
Stem Cell Subtypes in Skin Regeneration
Embryonic Stem Sells
Induced Pluripotent Stem Cells
Mesenchymal Stem Cells
Epithelial (Epidermal) Stem Cells
Applications in Defective Wound Healing
Stem Cells in Overscarring
Stem Cell Therapy in Pathological Scarring
Conclusion
Cross-References
References
5 Mesenchymal Stem Cells
Introduction
Mesenchymal Stem Cells: Fist Description in Bone Marrow
Bone Marrow-Derived MSCs
Isolation of MSCs from Different Sources
Adipose Tissue
Umbilical Cord
Umbilical Cord Blood
Wharton´s Jelly
Placenta
Characterization MSCs Before Culture
STRO-1
CD271
SSEA-4
CD146
MSCs in the Clinical Perspective
MSCs-Based Therapy for Cardiovascular Pathologies
MSCs-Based Therapy for Acute Graft-Versus-Host Disease
MSCs-Based Therapy for Crohn´s Disease
MSCs-Based Therapy for Multiple Sclerosis
MSCs-Based Therapy for Rheumatoid Arthritis and Osteoarthritis
Exosomes-Based Therapeutic Intervention
MSCs-Derived Exosome for Therapy ``Without Cells´´
MSCs-Derived Exosomes and Acute Graft-Versus-Host Disease
MSCs-Derived Exosomes for Inflammatory Bowel Disease
MSCs-Derived Exosomes for Rheumatoid Arthritis and Knee Osteoarthritis
MSCs-Derived Exosomes for the Heart
Multiple Sclerosis
Conclusion
References
6 Mesenchymal Stromal Cells for COVID-19 Critical Care Patients
Introduction
Mechanism of Infection and Immune Response
The Rationale for the Clinical Use of MSCs for COVID-19 Patients
Progress in MSC-Based Therapy for COVID-19
Other Cell-Based Innovation for COVID-19
Side Effects of Mesenchymal Stem Cell-Based Therapy
Unmet Challenges of Adoptive MSCs Therapy
Study Design
Source of Cells
Route of Cell Administration
Dosage Strategies
Risks Associated with Stem Cell Therapy
Concluding Remarks
References
7 Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease
Introduction
IBD Therapy with MSCs
MSCs Properties
Mechanisms of MSCs´ Action
Preclinical Studies
MSCs-Derived Exosomes for Experimental IBD Therapy
Clinical Studies
Completed Clinical Studies
Local MSCs Injections
Intravenous MSCs Administration
Proceeding Clinical Studies
Conclusion
References
8 Extracellular Vesicles-Based Cell-Free Therapy for Liver Regeneration
Introduction
Liver and Heart Connected and Non-connected Defects
Status on Cell-Based Therapy for Liver Diseases
Experimental Animal Studies
Clinical Studies
Cell-Free Therapy Approaches for the Liver
Diagnostic and Therapeutic Role of EVs in Liver Diseases
Conclusion and Future Perspectives
References
9 Current State of Stem Cell Therapy for Heart Diseases
Introduction
Aging of the Heart
Heart Disease
Conventional Therapies for Heart Disease
Mechanisms of Action of Stem Cells in Restoring the Heart Function
Clinical Evidence of Cell-Based Intervention in Ameliorating Heart Disease
Acute Myocardial Infraction
Heart Failure
Refractory Angina
Limitations of Stem Cell Therapy
Future Perspectives
Combination with Gene Therapy
Exosomes
Biomaterials
Conclusion
Cross-References
References
10 Mesenchymal Stem Cells for Cardiac Repair
Introduction
BM-Derived MSCs
Isolation and Characterization of MSCs
Important Characteristics of MSCs
Differentiation Potential of MSCs
Trophic Functions of MSCs
Immunomodulatory Characters of MSCs
Preclinical Studies with MSCs
Small Experimental Animal Studies
Large Animal Experimental Models: Translational Studies
MSCs in the Clinical Perspective
Randomized Clinical Trials with Autologous or Allogenic BM-Derived MSCs
The POSEIDON Trial
The PROMETHEUS Clinical Trial
The TAC-HTF Clinical Trial
Mesenchymal Stromal Cell for IHD
Intravenous Allogenic MSC Nonischemic Cardiomyopathy
Conclusions and Future Perspective
References
11 Preclinical Research of Mesenchymal Stem Cell-Based Therapy for Ocular Diseases
Introduction
Models of Corneal Diseases
Models of Lens Diseases
Retinal Models
Model Damage to the N-methyl-d-aspartate Receptor (NMDA)
Models of Transient Ischemia
Transgenic RGC Loss Models
Model of Experimental Autoimmune Encephalopathy (EAE)
Models of Hereditary Diseases Associated with Optic Nerve Damage
Glaucoma Models
Animal Models of Primary Angle-Closure Glaucoma (PACG)
References
12 Stem Cell for Cartilage Repair
Introduction
Cartilage
Chondrocyte
Collagen
Fluid
Chondrocyte Degeneration and Loss of Articular Cartilage
The Articular Cartilage Defects Treatments
Traditional Surgical Regeneration Techniques
Microfracture
Osteochondral Transplantation (OCT)
Osteochondral Autologous Transplantation (OAT)
Osteochondral Allograft Transplantation (OCA)
Particulated Articular Cartilage Implantation (PACI)
Tissue-Engineered Articular Cartilage
``Cell-Scaffold Construct´´ Strategies
Cell-Free Strategies
Scaffold-Free Strategies
Common Cell Types for Articular Cartilage Regeneration
Mature Cells
Stem Cells
Mesenchymal Stem Cells
BM-MSCs
WJ-MSCs
UCB-MSCs
SMSCs/SF-MSCs
Adipose Tissue-Derived MSCs
PB-MSCs
Scaffolds for Cartilage Treatment
Bioreactors
Spinner Flasks
Rotating Wall Vessels
Perfusion Bioreactors
Magnetic Field Bioreactors
Ultrasonic Bioreactors
Conclusion
Cross-References
References
13 Direct Reprogramming Strategies for the Treatment of Nervous System Injuries and Neurodegenerative Disorders
Introduction
Direct Neural Reprogramming Strategies
Reprogramming Factors
Transcription Factors
miRNA
Small Molecules
Approaches for Determining the Optimal Combination of Reprogramming Factors
Comparative Gene Expression Analyses
Trial and Error Screening of Libraries
CRISPR Activation-Based Screening
Employing Single-Cell RNAseq and Computational Analysis
Implications of the Cell Source
Fibroblasts
Astrocytes
Hepatocytes
Pericytes
Urine Epithelial Cells
Generation of Distinct Neural Cell Subtypes
Different Subtypes of Astrocytes
Different Subtypes of Oligodendrocytes
Potential Pitfalls in Autologous Cell Transplantation
Treating CNS Disorders Using Transdifferentiated Neural Cells
Spinal Cord Injury
Traumatic Brain Injury
Ischemic Stroke
Multiple Sclerosis
Parkinson´s Disease
Alzheimer´s Disease
Conclusions
Cross-References
References
14 Therapeutic Effects of Mesenchymal Stem Cells on Cognitive Deficits
Introduction
MSCs and Their Exosomes as New Therapeutic Agents in Regenerative Neurology and Neuroimmunology
Therapeutic Effects of MSCs and Their Exosomes in the Treatment of Alzheimer´s Disease
Improvement of Cognitive Impairment Following Brain Damage and Ischemia in MSC-Treated Mice
Therapeutic Effects of MSCs and MSC-Exos in the Treatment of Parkinson´s Disease, Schizophrenia, and Autism
Conclusion
References
15 Augmenting Mesenchymal Stem Cell-Based Therapy of the Infarcted Myocardium with Statins
Introduction
Stem Cell-Based Therapy for Myocardial Repair
Mesenchymal Stem Cells in Myocardial Repair and Regeneration
Poor Survival of Stem Cells Postengraftment
Strategies to Enhance Donor Cell Survival
Stem Cell Preconditioning
Augmenting the Myocardial Microenvironment Favorable for Donor Cells
Statins as Preconditioning Mimetic and Modifier of Myocardial Microenvironment
Introduction to Statins
Functional Mechanism of Statins
The Impact of Statins on Mesenchymal Stem Cells
Statins and Stem Cell Preconditioning
Statins and In Vitro Experimental Studies
Statins and in vivo Experimental Animal Models
Combined Statin and MSCs-Based Cell Therapy
Using Statin-Preconditioned MSCs to Treat AMI
Statin-Based Preconditioning of MSCs and Exosomes
Combined Statin and Cell-Based Therapy for AMI Patients
Conclusion and Future Perspective
Cross-References
References
16 Unraveling the Mystery of Regenerative Medicine in the Treatment of Heart Failure
Introduction
Heart Failure
Regenerative Potential of Stem Cells
Endogenous Cardiac Regeneration
Outcomes of Clinical Studies
Pluripotent Stem Cells
Skeletal Myoblasts
Bone Marrow-Derived Stem Cells
Mesenchymal Stem Cells
Cardiac Stem Cells
Understanding the Factors Affecting Cell-Based Therapy
Engraftment, Survival, and Rejection
Dosage
Cell Type
Route of Administration
Hippo-YAP Pathway
Ethical Issues in Regenerative Medicine
What Does the Future Hold for Cardiac Regenerative Medicine?
Cell-Free Strategies
Bioengineering
Conclusion and Future Perspectives
References
17 Therapeutic Uses of Stem Cells for Heart Failure: Hype or Hope
Introduction
Pathophysiology of Heart Failure
Significance to the Research
Introduction to Stem Cells
Embryonic Stem Cells
Induced Pluripotent Stem Cells
Adult Stem Cells
Endogenous Regeneration of Cardiomyocytes
Landmark Clinical Trials
Adult Stem Cells
Cardiac Stem Cells
Bone Marrow-Derived Cells
Mesenchymal Stem Cells
Skeletal Myoblasts
Pluripotent Stem Cells
Embryonic Stem Cells
Induced Pluripotent Stem Cells
Insights into Ccell-Based Therapy Approaches
What Is the Proposed Mechanism of Action?
Paracrine Signaling
Direct Regeneration
Optimizing Cardiac Stem Cell Therapy
What Is the Optimal Cell Type?
What Is the Optimal Method of Delivery?
What Is the Appropriate Timing of Administration?
Patient Characteristics and Sourcing
What Are Some Challenges that Remain?
What Are Some Ethical Considerations in Using Stem Cells?
False Claims
Conclusion
References
18 Mesenchymal Stem Cell-Probiotic Communication: Beneficial Bacteria in Preconditioning
Introduction
Identification, Isolation, and Biology of OMT-Derived Stem Cells
Preconditioning Strategies
Probiotics and their Health Benefits Associated with Gut Microbiota
Mesenchymal Stem Cells-Probiotic Interaction
Future Perspective and Conclusion
References
19 Effects of 3D Cell Culture on the Cell Fate Decisions of Mesenchymal Stromal/Stem Cells
Introduction
3D Cell Culture of MSCs
Impact of 3D Cell Culture on Cell Fate Decisions of MSCs
Viability and Proliferation
Cellular Senescence
Osteogenic Differentiation
Adipogenic Differentiation
Chondrogenic Differentiation
MSC-Secretome, Immunomodulation, and Anti-Inflammatory Potential
Conclusions
Cross-References
References
Part II: Cell-Based Therapy Approach: Non-Mesenchymal Stem Cell-Based Therapy
20 The Function of Stem Cells in Ocular Homeostasis
Introduction
Cornea
Corneal Epithelium
Corneal Stroma
Corneal Endothelium
Conjunctiva
Iris
Ciliary Body
Trabecular Meshwork
Lens
Retina
Retinal Pigment Epithelium
Retinal Muller Cells
Summary
Cross-References
References
21 The Potential of Stem Cells in Ocular Treatments
Introduction
Cornea
Corneal Epithelium
Corneal Stroma
Stem Cell-Based Treatment for Corneal Edema
Trabecular Meshwork
Ocular Lens
The Retina
Conclusion
Cross-References
References
22 Myoblast Therapies Constitute a Safe and Efficacious Platform Technology of Regenerative Medicine for the Human Health Indu...
Introduction
Gene Defect: The Original Sin
Genetic Diseases Account for >80% of Human Death
Approaches Towards Treatment
Autografts Cannot Treat Genetic Diseases
Treatment Design and Mechanisms
Why Cell Therapy
Myoblasts: Nature´s Chest of Gene Medicine
MTT Platform Technology
Replenishing Dead Cells
Repairing Hereditary Degenerative Cells
Engineering Genetic Mosaicism with MTT: Supply of Normal Genome via Injection of Myoblasts
Original Testing of Idea
Pertinent Muscle Developmental Biology
Myogenesis
Neuromuscular Transmission
Excitation Contraction Coupling
Number of Myofibers and Strength
Parameters Governing Cell Fusion
Controlled Cell Fusion
Mitotic Cardiomyocytes via In Vitro Controlled Cell Fusion
Injection Methods Regulate Cell Distribution and Fusion
Cyclosporine Immunosuppression
Muscular Dystrophy
Etiology
Pathogenesis: Cell Membrane Defect
Duchenne Muscular Dystrophy
Natural History
Strategizing DMD Treatment
Induction of Genetic Mosaicism
Normal and Dystrophic Minced Muscle Mixes
Newborn Muscle Transplant
Mesenchymal Cell Transplant
MTT with Primary Myoblast Culture
MTT in DMD Subjects
Single Muscle Treatment (SMT): Phase I Trial
Lower Body Treatment (LBT): Phase II Trial
Whole Body Treatment (WBT): Phase II and III Trials
Rationale
Dose Escalation
Objective
Study Design
UBT/LBT Randomization
Myoblast/Placebo Randomization
Donors
Myoblast Preparation
The 25 Billion Myoblast WBT Protocol
The 50 Billion Myoblast WBT Protocol
WBT Significance
Heart Muscle Degeneration
Severe Myocardial Infarction
Proof-of-Concept for AMT
AMT Is Safe and Efficacious with MI Patients
AMT Is Safe and Efficacious with End-Stage HF Subjects
Regulatory
Case Selection
Patient Selection
Manufacture of Allogeneic Human Myoblasts
Cyclosporine Immunosuppression
Clinical Research Procedures
AMT
Data Analysis and Interpretation
Statistical Analyses
Safety Assessment
Efficacy Assessment
Understanding and Debating the Study Outcomes
Perspectives
Conclusion
Angiomyogenesis
Autonomous Robotic Cell Injection Catheter System
Cellular and Molecular Phases of MTT Development
MTT Corrects Gene Defects in Type II Diabetes
Type II Diabetes
MTT in Type II Diabetes Human Study
MTT Use in Drug Discovery
Multiple Usage of MTT in Genetic Diseases
Preliminary Safety and Efficacy Data of MTT in Cancer Treatment
Identification of the Polygenic Defects of Various Cancer
Myoblasts Inhibit Metastasis, Tumor Growth, and Induce Cancer Apoptosis
Myoblasts Fuse with Cancer Stem Cell
Plausible Sequence of Events
MTT in Breast and Uterine Cancers
Conclusion
Antiaging Aesthetica
In Law´s Enchanting World of MTT
Personalized Medicine for Each Family
Biologic Skin
Body Sculpture
Be More Macho
Be More Feminine
Tendon Repair for Injured Athletes
Loose Teeth and Bone Fracture Repair
Stimulation Therapies and Fractal Dynamics to Complement MTT Treatment of Diseases
MTT Replenishes Mitochondria and Regenerates Energy Network of Life
Intellectual Property Portfolio of Professor Peter K. Law
FDA, EMA Approved MTT IND´s
Conclusion
References
23 Adipose Tissue-Derived Regenerative Cell-Based Therapies: Current Optimization Strategies for Effective Treatment in Aesthe...
Introduction
AT-Derived Regenerative Cells
Adipose-Derived Stem Cells
Current Regulatory Considerations for the Production and Clinical Application of SVF/ASCs
Assessing the Therapeutic Potential of SVF/ASCs in Aesthetic Surgery
Safety Concerns with the Use of Culture-Expanded ASCs for Cell Therapy
Clinical Application of SVF/ASCs in Aesthetic Surgery
Soft Tissue Reconstruction
Use of ASCs in Re-contouring Depressed Facial Lesions
ASCs in Wound Healing
Bone Reconstruction
Cross-References
References
24 Molecular Signature of Stem Cells Undergoing Cardiomyogenic Differentiation
Introduction
Basic Structure of Cardiomyocytes
Atrial and Ventricular Cardiomyocytes
Stem Cells and Cardiac Regenerative Therapy
Embryonic Stem Cells and Their Derivative CMs
iPSCs and Their Derivative Cardiomyocytes
Adult Tissue-Derived Stem/Progenitor Cells
Molecular Profiling of Cardiomyocytes
Cardiomyocyte Lineage Commitment and Differentiation
Bone Morphogenetic Proteins (BMPs)
Wnt Pathway
Fibroblast Growth Factor Signaling Pathway
Cardiac-Specific Transcription Factors
GATA Family of Transcription Factors
Myocyte Enhancer Factor-2 (MEF-2) Family
NKX-2.5
Serum Response Factor and Myocardin
HAND Transcription Factors
Two-Dimensional (2D) Differentiations of Stem Cells into Cardiomyocytes
Status of iPSC-Derived Cardiomyocytes
Current Technical Limitations
State of the Art
Regulation of Lineage Differentiation in Stem Cells
Differentiation Cues
Small Molecule Inhibitors
Role of Small Molecule Inhibitors in Stem Cell Biology
Microenvironment
Exosomes for In Vitro and In Vivo Cardiac Applications
Detailed Methodology
Functional Maturation Analysis
Morphological Analysis
Functional Analysis
Metabolic Analysis
Cardiomyocyte Maturation-Specific Gene Expression Analysis
Limitations of 2D Culture
3D Cardiac Organoids
Working on the 3D Models
Scaffolds Employed
Analytical Methods
Conclusions and Outlook
References
25 Stem Cell Applications in Cardiac Tissue Regeneration
Introduction
Engineering of Infarcted Myocardium
MSCs in Cardiac Regenerative Therapy
Natural and Synthetic Polymer Used for Regenerative Therapy
Natural Scaffolds
Extra-Cellular Matrix (ECM)
Collagen Scaffolds
Synthetic Scaffolds
Hydrogel Based Therapy
Patch-Based Cell Therapy
3D-Bioprinting
The Complexity of the Cardiac Tissue
3D-Printing Salient Points
3D Printing Techniques of Heart Tissue
Bioinks for Heart Tissue
Conclusion and Future Directions
Cross-References
References
26 Vascular Functional Recovery and Reparation by Human Endothelial Progenitor Cells
Introduction
Endothelial Progenitor Cells: Definition and Biological Function
Endothelial Progenitor Cell Dysfunction in Cardiovascular Diseases
Early Outgrowth and Endothelial Colony-Forming Progenitor Cells in Revascularization and Vascular Reparation
Animal Studies for Vascular Repair with EPCs
Clinical Studies for EPCs Applications
Conclusion and Future Prospects
References
27 Neural Stem Cells
Introduction
Historic Prospective of Neural Stem Cells
Neural Stem Cell Culture - Its Applications and Limitations
Influence of the Microenvironment and Niche on Embryonic NSCs - Intrinsic Regulation
Signaling Molecules That Affect NSC Differentiation
Extracellular Matrix (ECM) Role in Regulating Neural Stem Cell Characteristics
Anomalies in Neurogenesis and Brain Pathologies
Advances in Neural Stem Cell Transplantation and Therapy (Fig. 1 and Table 3)
Conclusions
References
28 Glial Cells in Neuroinflammation in Various Disease States
Introduction
Microglial Cells and Their Physiological Functions
Physiological Roles of Astrocytes
Reactive Gliosis in Astrocytes
Stroke, CNS Trauma, and Their Impact on Glial Cells
Roles of Glial Cells in CNS Autoimmune Conditions
Roles of Glial Cells in Neurodegenerative Disorders
Current Therapies for CNS Disorders
Treatments for Stroke and CNS Trauma
Treatments for CNS Autoimmune Conditions
Treatments for Neurodegenerative Disorders
Cell-Based Therapies for CNS Disorders
Conclusion
References
29 Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform for Modeling Arrhythmias
Introduction
Establishing Patient-Derived hiPSC Lines
hiPSC Reprogramming
hiPSC Quality Control and Genotyping
Genome Editing Applications
hiPSC-CM Differentiation, Purification, and Maturation
Differentiation and Definition of Homogenous Cardiomyocyte Subpopulations
Maturation
Phenotypic Assays
Transcriptomic and Proteomic Analysis
Metabolic Considerations
hiPSC-CM Morphology
Contractility and Force Generation
Electrophysiological Measurements and Arrhythmia Assessment
hiPSC-CMs for Proarrhythmic Drug Assessment
Conclusion
Cross-References
References
30 Induced Pluripotent Stem Cells
Introduction
From Classical Transcription Factor Quartet Transduction to Small Molecule Manipulation Protocols
iPSCs´ Limitations - Overcoming Barriers to Clinical Translation
Low-Efficiency Reprogramming of Somatic Cells
Tumorigenicity
Immunogenicity
Economic Issues and Biobanking iPSCs
Heterogeneity
Harnessing the Potential of iPSCs
iPSC-Based Disease Modeling, Drug Discovery, and Toxicity Studies
iPSC-Based Cell Therapy - Ongoing Clinical Trials
Conclusion
Cross-References
References
31 Human Stem Cell Differentiation In Vivo in Large Animals
Introduction
Long-Term Transplantation Tolerance Following Intrauterine Transplantation (IUT)
What Is a Stem Cell?
Why a Large Animal?
IUT as an Experimental Tool to Study SC Biology or What Is a Stem Cell Revisited
The Hematopoietic SC (HSCs)
The Mesenchymal Stem Cell (MSC)
Stem Cell Plasticity
What Is Stem Cell Plasticity, and How Can It Be Explained Physiologically
IUT as a Clinical Option
Conclusion
Cross-References
References
Part III: Cell-Free Therapy Approach
32 Mesenchymal Stem Cell-Extracellular Vesicle Therapy in Patients with Stroke
Introduction
Advantages of EVs over MSCs in Stroke
Evidence of the Role of Stem Cell-Derived EVs in Stroke
Preclinical Evidence of EV Therapeutics in Stroke Models
Clinical Evidence of EV Efficacy in the Clinical Trial of MSCs in Stroke Patients
Status and Limitations of EV Therapeutics
Preclinical Studies
Clinical Studies
Considerations for the Application of EV Therapeutics in Stroke
Current Guidelines/Recommendations
Quality Control and Potency Markers
RNAs
Proteins
Other Cargos
Isolation, Dosage, Mode of Application, and Biodistribution
Production of EV Preparation
Isolation of Prepared EVs
Recent Advances in EV Therapeutics
Conclusions and Perspective
References
33 Mesenchymal Stem Cell Secretome: A Potential Biopharmaceutical Component to Regenerative Medicine
Introduction
MSCs´ Roots
MSCs´ Biological Properties
The Pitfalls of MSCs
Secretome Derived from MSCs as Cell-Free-Based Therapeutic Strategy
Composition and Characterization of MSCs´ Secretome
The Soluble Fraction: Cytokines and Growth Factors
The Vesicular Fraction: Extracellular Vesicles
The Vesicular Fraction: Coding and Non-coding RNAs
Mechanisms of Action and Principal Effects
Pre-clinical Approaches of Mesenchymal Stem Cell Secretome
Wound Healing and Cartilage Repair and Regeneration
Cardiovascular Diseases
Kidney and Lung Injuries
Central Nervous System Pathologies
Traumatic Brain Injury (TBI)
Spinal Cord Injury (SCI) and Ischemic Stroke (IS)
Neurodegenerative Disorders
Clinical Approaches Based on Mesenchymal Stem Cell Secretome
The Benefits and Barriers of MSCs´ Secretome
Improvements Needed for Secretome Application as a Cell Transplantation-Free Tool
Conclusion
Cross-References
References
34 Exosome-Based Cell-Free Therapy in Regenerative Medicine for Myocardial Repair
Introduction
Cell-Based Therapy for the Heart
Cell-Free Therapy Approach for the Heart
Theranostic Role of Exosomes in the Heart
Diagnostic Applications of Exosomes
Exosomes as a Treatment Option for the Injured Heart
Exosome in Experimental Animal Heart Models
Exosome in Translational Experimental Studies
Exosome in Clinical Studies
Challenges and Future Perspective
Cross-References
References
35 Current Trends and Future Outlooks of Dental Stem-Cell-Derived Secretome/Conditioned Medium in Regenerative Medicine
Introduction
Dental Stem/Progenitor Cells (DMSCs)
Stem/Progenitor Cells´ Secretome/Conditioned Medium
Extracellular Vesicles (EVs)
Exosomes (EXs) and Microvesicles (MVs)
Comparison Between Secretome/CM Derived from DMSCs and MSCs from Other Tissue Sources
Secretome/Conditioned Medium (SHED-CM) Derived from Stem Cells from Exfoliated Human Deciduous Teeth
SHED-CM in Treating Cardiopulmonary Injuries
SHED-CM in Treating Hepatic Disorders
SHED-CM in Treating Diabetes Mellitus
SHED-CM in Treating Immunological Disorders
SHED-CM in Treating Dental-Pulpal Disorders
SHED-CM in Treating Neural Injuries
Secretome/Conditioned Medium Derived from Dental Pulp Stem Cells
The Osteogenic Potential of DPSCs-CM
DPSCs-CM in the Treatment of Liver Disorders
Potential of DPSCs-CM to Regenerate Dental Tissues
The Role of DPSCs-CM in the Treatment of Neurological Diseases
DPSCs-CM in the Treatment of Autoimmune Diseases
Secretome/Conditioned Medium Derived from Gingival Mesenchymal Stem/Progenitor Cells
GMSCs-CM in Treating Neural Disorders
GMSCs-CM in Treating Skin Injuries
GMSCs-CM Osteogenic Potential
Periodontal Ligaments Stem-Cell-Derived Secretome/Conditioned Medium
PDLSCs-CM in the Therapy of Neural Disorders
PDLSCs-CM Osteogenic Potential
PDLSCs-CM in Dental Tissue Regeneration
Secretome/Conditioned Medium Derived from Stem/Progenitor Cells of Apical Papilla (SCAP), Dental Follicle Stem/Progenitor Cell...
Conclusions
References
36 Extracellular Vesicles Derived from Mesenchymal Stem Cells
Introduction
Extracellular Vesicles
Mesenchymal Stem Cell-Derived Extracellular Vesicles
Role of Mesenchymal Stem Cell-Derived EVs in Regeneration
Immunosuppressive Activity of EVs
EV-Mediated Mitochondria Donation by MSCs
Approaches of Large-Scale Production of Vesicles
Cytochalasin B-Induced Membrane Vesicles
Vesicle Production by Mechanical Extrusion
Vesicle Production Using a Hyperosmotic Solution
Conclusion and Future Directions
Cross-References
References
37 Skeletal Muscle-Extricated Extracellular Vesicles: Facilitators of Repair and Regeneration
Introduction
Skeletal Muscle Repair and Regeneration
General Introduction to Skeletal Muscle Regeneration Events
The Role of (Other) Residential Cells
The Immune Response
Macrophages and Lymphocytes
The Case for Muscular Dystrophy
Myofiber Intracellular Repair
Extracellular Vesicles
Proteins and Lipids
RNA Cargo
Uptake of Vesicles by Target Cells
EVs Released by Different Cells in the Injured Muscle Environment
The Inflammatory Response via EVs and Subsequent Activation of Nearby Cells
Conclusion
References
38 Regenerative Medicine Applied to the Treatment of Musculoskeletal Pathologies
Introduction
Mesenchymal Stem Cells Based Therapies: A Useful Tool?
MSCs Secretome as an Alternative to Cell-Based Therapy
Soluble Factors Secreted by MSCs
Immunomodulation
Angiogenesis and Revascularization
Anti-apoptotic Activity
Extracellular Vesicles
Composition of EVs Cargo
Applications of the Secretome from Mesenchymal Stem Cells in the Treatment of Musculoskeletal Diseases
MSCs Secretome for Bone Regeneration
MSCs Secretome in the Treatment of Cartilage Defects and Cartilage Degeneration
MSCs Secretome in the Treatment of Tendon Injuries
Modulating Secretome Therapeutic Properties
Hypoxia Induction
Inflammatory Priming
Addition of Bioactive Factors
Modulation of Cell-Cell Interactions
Tuning Cell-Substrate Interaction (ECM and Scaffolds)
Genetic Editing
Disease-Like Priming
Future Perspectives
References
Part IV: Miscellaneous Aspects of Stem Cell Applications
39 Common Ethical Considerations of Human-Induced Pluripotent Stem Cell Research
Introduction
Safety
Reproduction
Patentability
Informed Consent and Donors´ Right
Conclusion
Cross-References
References
40 Response of the Bone Marrow Stem Cells and the Microenvironment to Stress
Introduction
Bone Marrow Microenvironment
Components of the Bone Marrow Microenvironment
Different Stem Cell Niches in the BM Microenvironment and Their Spatial Position
Dynamic Interactions in the BM Microenvironment
Bone Marrow and Stress Response
Cell and Microenvironment Response to Stressors
Hematopoietic Stress Response
Emergency Hematopoiesis
Environmental Hematopoietic Stressors
Environmental Pollutants
Benzene
Nanoparticles and particulate matter
Dioxins as Persistent Organic Pollutants (POPs)
Polycyclic Aromatic Hydrocarbons (PAH)
Heavy Metal Exposure
Detoxification Response and Signaling Pathways
Drug metabolizing enzymes Cytochrome P450 (CYP) and Glutathione S-Transferases (GSTs)
Aryl Hydrocarbon Receptor (AhR)
Toll-like receptor (TLR) Signaling
BM Microenvironment Alterations, Dysregulation, and Myeloid Leukemia
Development of Secondary Myeloid Malignancy
Therapy-Related Myeloid Malignancy
Leukemia-Predisposing Inherited BM Failure Syndromes
Fanconi anemia
Shwachman-Diamond syndrome
BM Microenvironment as a Contributor/Driver of Leukemia
Metabolic Dysregulation and the Role of Adipocytes in the Malignant Niche
Marrow Adipose Tissue and Leukemia
Environmental Stressors and Adipose Tissue
Conclusions
References
41 Advances, Opportunities, and Challenges in Stem Cell-Based Therapy
Introduction
Mesenchymal Stem Cells
Mesenchymal Stem Cells Sources
The Therapeutic Potential of Mesenchymal Stem Cells
Application of Mesenchymal Stem Cells in Medicine
MSC-Based Therapies in Graft Versus Host Disease
Mesenchymal Stem Cell-Based Therapies in Crohn´s Disease
Mesenchymal Stem Cell-Based Therapies in Cardiology
Mesenchymal Stem Cells-Based Therapies in Orthopedics
MSC-Based Therapies in Neurology
Potential Risks of MSC-Based Therapies
Conclusions
References
42 The Stem Cell Continuum Model and Implications in Cancer
Introduction
The Stem Cell Continuum
Extracellular Vesicle Basics
Extracellular Vesicle Functions
Extracellular Vesicle Pleiotropy and Regenerative Potential
Extracellular Vesicles Affect Normal Stem Cells
Extracellular Vesicles Affect Cancer Stem Cells
An Introduction to Extracellular Vesicles and Hematological Malignancies
Extracellular Vesicles in Leukemia
The Leukemic Bone Marrow Microenvironment
Predictors of Response and Promoters of Resistance in Leukemia
Extracellular Vesicles in Lymphoma
The Lymphoma Tumor Microenvironment
An Introduction to Extracellular Vesicles and Breast Cancer
Role of TEVs in Breast Cancer
Use of TEVs in Breast Cancer Treatment
Use of TEVs for Diagnostic and Predictive Markers in Breast Cancer
An Introduction to EVs and Lymphoma
Extracellular Vesicles in Primary CNS Lymphomas
The Role of EVs in Diagnosis and as a Biomarker in Primary CNS Lymphoma
Extracellular Vesicles´ Function on Lymphomagenesis and Lymphoma Treatment Response
EVs´ Effects on Lymphoma Patient Outcomes and Prognosis
Role or Target in Therapy for Lymphoma
Lymphoma-Specific EV Roles
Diffuse Large B-Cell Lymphoma (DLBCL)
Virally Mediated Lymphomas
Hodgkin´s Lymphoma (HL)
References
43 Toll-Like Receptor 3
Introduction
Mesenchymal Stem Cells
Toll-Like Receptor 3 and Its Activation Pathways
TLR3 Priming and MSC Immunomodulation
TLR3 Priming and MSC Differentiation
TLR3 Priming and MSCs´ Migration and Proliferation
TLR3-Mediated Apoptosis and Survival of MSCs
Micro-RNAs as Modulators of TLR3-Mediated Response in MSCs
Conclusion
References
44 Targeting Cancer Stem Cells: New Perspectives for a Cure to Cancer
Introduction
Role of Cancer Stem Cells (CSCs) in the Tumor
Markers in CSCS: A New Approach Against Tumor
Targeting CSCs
The Hedgehog Signaling Pathway
The Notch Signaling Pathway
The Wnt Signaling Pathway
Targeting ALDH as the Drug-Detoxify Enzymes Against CSCs
Targeting Drug Efflux Pumps
Targeting the CSC Niche and the Quiescent State
An Update on the Most Used Target Therapies Against CSCs
Oncolytic Adenovirus
Oncolytic Herpes Simplex Viruses
Oncolytic Virus and Its Effects in Recent Clinical Trials
Oncolytic Adenoviruses and Pancreatic Clinical Trials
Oncolytic Herpes Simplex Viruses and Pancreatic Clinical Trials
Stem Cell-Derived Exosomes as Therapeutic Carriers
Conclusions and Future Directions
References
45 Bioengineering Technique Progress of Direct Cardiac Reprogramming
Introduction
Pluripotent Stem Cells in Myocardial Regeneration and Repair
The Strategy of Direct Reprogramming to Generate Cardiomyocytes
Observations and Data Analysis
Synthesis and Characterization of CMBs and Lentivirus-Binding Capacity
Reprogramming of Rat CFs into iCMs by the GMT Lentivirus Vectors In Vitro
UTMD-Mediated Localized Delivery of Direct-Reprogramming GMT Lentivirus-CMB Hybrids In Vivo
Histological Assessment of Post-Infarct Ventricles After UTMD Therapy
Cardiac Function Improvement After UTMD-Mediated Direct Reprogramming Therapy
Significance of the Combinatorial Approach of UTMD with CMB-Lentiviral Hybrid
CMB-Lentivirus Hybrids in Gene Delivery
Advantages of Lentiviral Vectors for Direct Reprogramming
Improvement of Reprogramming Factors in Direct Cardiac Reprogramming
Ultrasound-Mediated Localized Direct Reprogramming via Lentivirus Delivery for Cardiac Repair
Conclusion and Future Perspective
A Summary of the Experimental Methods and Design
Vectors and Cells
Creation of CMBs and Microbubble-Virus Hybrids
Direct Reprogramming of CFs In Vitro
A Western Blot Analysis
Development of Experimental Rat Model of MI
Delivery of Microbubble-Lentivirus Hybrids Using UTMD In Vivo
Histological Examination
Cardiac Magnetic Resonance Imaging (cMRI) and Echocardiography
References
46 Future Perspectives of Exosomal Payload of miRNAs in Lung Cancer
Introduction
Exosome Composition
Biological Functions of Exosomes
Exosomes and Cancer
The Pathways of Exosomal miRNA Secretion
Exosomal miRNAs in Cancer Progression
Tumor-Derived Exosomes and Lung Cancer
Future Perspectives of Exosomal miRNAs in the Clinics
References
47 Endothelial Progenitor Cells from Bench to Antitumor Therapy and Diagnostic Imaging
Introduction
Stem Cells
An Overview of Endothelial Progenitor Cells
Endothelial Progenitor Cells in Neovascularization
Endothelial Progenitor Cells Applications
Endothelial Progenitor Cells Sources, Ex Vivo Culturing, and Implantation
Endothelial Progenitor Cells in Preclinical Cancer Studies
Side Effects and Potential Risks of EPCs Cell Therapy
Conclusion and Future Perspective
References
48 Non-cryopreserved Peripheral Stem Cell Autograft for Multiple Myeloma and Lymphoma in Countries with Low Resources
Introduction
Bibliographic Literature Search for the Chapter
Data Analysis from the Selected Studies
Cell Mobilization
Apheresis
Cell Storage
Cell Viability
Conditioning Regimen
Cell Engraftment
Posttransplant Data
Comparative Studies
The Study by Sarmiento et al. (2018)
The Study by Bittencourt et al. (2019)
The Study by Bekadja et al. (2021)
The Study by Garifullin et al. (2021)
An In-Depth Analysis of the Published Data
Cell Mobilization
Conservation and Cell Viability
Therapeutic Intensification
Donor Cell Engraftment
Conclusion and Future Perspective
References
49 A Multilevel Approach to the Causes of Genetic Instability in Stem Cells
Introduction
DNA Damage Response in Stem Cells
Factors That Influence DNA Stability in Stem Cells
Oxidative Stress
Senescence as a Factor Inducing Stem Cells Genomic Instability
Aging and Genomic Instability in Stem Cells
Telomere Damage and Genetic Instability in Stem Cells
Aneuploidy as an Expression of Genome Instability
Influence of Genomic Arrangement in the Nucleus on Aneuploidy
Lamins Alterations and Aneuploidy
Replicative Stress/Replication Timing as Causes of Genome Instability
Cell Origin as Source of Genome Instability
Adipose Stem Cells (ASC)
Embryonic Stem Cells
Induced Pluripotent Stem Cells
Effect of Reprogramming Methods on Genetic Instability
Mutations Induced During Reprogramming
Culture Conditions, the Passage Number
The Bystander Effect
Instability Factors Related to Donors
Obesity
Donor Age
Toxic Habits and Diseases in the Donors
Conclusion
Cross-References
References
Index