Stem Cells: Latest Advances

Description

In this volume, the contributing authors from top labs involved in stem cell theranostics share the latest advances in the field of stem cell research. The book covers many aspects of stem cell-based therapy and the progress made toward stem cell therapy for liver, ocular, and cardiovascular diseases as well as cancer. This volume serves as a continuation of Prof. Khawaja Husnain Haider’s previously edited books pertaining to stem cells-based therapnostics. This is an ideal book for researchers involved in drug development as well as regenerative medicine and stem cell-based therapy. The secondary audience includes graduate and postgraduate medical students, doctors, cellular pharmacology, drug industry, and researchers involved in using stem cells as ex-vivo disease models for drug development. Preface Contents 1: Microelectrode Arrays: A Valuable Tool to Analyze Stem Cell-Derived Cardiomyocytes 1.1 Introduction 1.2 Methods for the Electrophysiological Characterization of hiPSC-CMs 1.2.1 Dye-Based Assessment of the Membrane Potential 1.2.2 Patch-Clamp Recordings 1.2.3 Whole Tissue Measurement with Extracellular Electrodes 1.3 MEA-Based Characterization of Physiological Parameters 1.3.1 The Field Potential Describes Cellular Electrophysiology 1.4 MEA-Based Evaluation of Drug-Induced Cardiotoxicity 1.4.1 CIPA—A New Paradigm in Cardiotoxicity Drug Screening 1.4.2 hiPSCs—An In Vitro System to Simulate Human Cardiac Physiology 1.5 Personalized Medicine 1.6 hiPSCs as In Vitro Cell Models for CVDs 1.6.1 Selective Overview of Current iPSC-Based Cell Models for CVDs 1.7 Conclusion and Future Perspective References 2: CD34+ Stem Cells and Regenerative Medicine 2.1 Introduction 2.1.1 History 2.2 CD34+ Stem Cells and Peripheral Blood Stem Cell Transplantations 2.2.1 Evolution in CD34+ Stem Cell Knowledge 2.2.2 CD34+ Stem Cells and Ischemic Diseases 2.2.2.1 Heart Diseases 2.2.2.2 Stroke 2.2.2.3 Critical Limb Ischemia 2.2.3 CD34+ Cells and Non-Ischemic Diseases 2.2.3.1 Liver Insufficiency 2.2.3.2 Knee Arthrosis 2.3 Very Small Embryonic-Like Stem Cells 2.4 Conclusion References 3: Mesenchymal–Hematopoietic Stem Cell Axis: Applications for Induction of Hematopoietic Chimerism and Therapies for Malignancies 3.1 Introduction 3.2 Hematopoietic Stem Cell and Bone Marrow Transplantation 3.2.1 Bone Marrow Transplantation 3.2.2 Bone Marrow Transplantation Challenges 3.2.3 Hematopoietic Stem Cell: History and Subtypes 3.3 Advancement of Conditioning Regimens for Bone Marrow Transplantation 3.3.1 Myeloablative Regimens for Malignant Cell Destruction and Allogeneic HSC Engraftment 3.3.2 Myeloablative vs Non-myeloablative vs Reduced Intensity Conditioning 3.3.3 Incorporating Monoclonal Antibody Therapy into RIC 3.4 Bone Marrow Dynamic Structure: HSC and MSCs Niches, Cells, Mechanisms, and Cross-Talk 3.4.1 Hematopoietic Stem Cell Niches 3.4.2 MSPCs and Their Role in HSC Niches 3.5 Endosteal/Osteoblastic HSC Niches 3.5.1 Osteoblasts 3.5.2 Osteoclasts 3.6 Nestin and Leptin 3.6.1 Perivascular HSC Niches 3.6.2 Leptin Receptor (LepR) 3.7 NG2 3.8 Sca-1 (Ly-6 A/E) 3.9 SCF/c-Kit 3.10 CXCL12 3.11 Challenging the Dogma of Necessity to Clear Space in HSC Niches for Engraftment of the Donor-Derived Hematopoiesis 3.11.1 Myeloablation and Its Impact on Multipotent HSCs 3.11.2 Myeloablation as a Means to Establish Niche Space for Allogeneic HSC Engraftment 3.11.3 Prevention of GVHD by Eliminating Donor-Derived Effector Cells and Supplementing Donor HSC Populations with Cell Subsets Aiding/Facilitating Their Engraftment 3.12 Potential Benefits of Clinical Adaptation of the MSPCs into Cytoreductive Therapies for Malignancies and Protocols for Induction of Allogeneic Hematopoietic Chimerism 3.12.1 MSPCs to Support Reconstitution of the Autologous Hematopoiesis Under Cytoreductive Therapies for Malignancies 3.12.2 MSPCs for Promoting Induction of Allogeneic Hematopoietic Chimerism 3.13 Summary and Conclusions References 4: Mesenchymal Stem Cell-Derived Secretome: A New Remedy for the Treatment of Autoimmune and Inflammatory Diseases 4.1 Introduction 4.2 Therapeutic Potential of MSCs 4.3 Modulation of Immune Cell Phenotype and Function by MSC-Derived Secretome 4.4 MSC-Derived Secretome as a New Therapeutic Agent: Evidence Provided by Animal Studies 4.5 Clinical use of MSC-Derived Secretome 4.6 Conclusion and Future Directions References 5: Cardiac Regenerative Therapy in Diabetes: Challenges and Potential Therapeutics 5.1 Introduction 5.2 Regenerative Therapy Approaches 5.2.1 Presence of Resident CSCs 5.2.2 Mechanical Scaffold and Cardiac Regeneration 5.2.3 Stem Cells and Cardiac Regeneration 5.2.4 Altering Resident Cells to Improve Cardiac Function 5.3 Differences in the Diabetic and nondiabetic Heart 5.3.1 The Heart Is a Highly Metabolically Active Organ 5.3.2 DM also Alters the Microenvironment of Myocardium 5.3.3 Diabetes and Heart Function Control 5.4 Challenges and Potential Therapeutic Strategies for Cardiac Regeneration in the Diabetic MI Heart 5.4.1 The Metabolic Status of the Transplanted Cells 5.4.2 The Toxic Microenvironment in the Diabetic Heart and Cell Survival 5.4.3 DM Reduces Contractility of Cardiomyocytes 5.5 Future Directions 5.5.1 Limitations of Current Approaches 5.5.2 Pitfalls and Alternatives of Current Regenerative Approaches 5.5.3 New Aspects to Consider Improving Regenerative Therapy 5.5.3.1 The Timing of Treatment 5.5.3.2 DM Causes Several Comorbidities 5.5.3.3 Key Aspects For Regenerating Diabetic Myocardium References 6: Macrophage Response to Biomaterials in Cardiovascular Applications 6.1 Introduction 6.2 Role of Monocyte/Macrophages in Cardiac Repair 6.3 Biomaterials–Monocyte Interaction and Monocyte/Macrophage Differentiation 6.4 Biomaterials in Cardiac Repair and Regeneration 6.4.1 Synthetic Biomaterials 6.4.1.1 Degradable Polymer Poly(Lactic Acid) (PLA) Nanofiber Polyurethane Patches 6.4.1.2 Non-Degradable Polymer Polyethylene Glycol (PEG) Expanded Polytetrafluoroethylene Polyethylene Terephthalate 6.4.2 Natural Biomaterials 6.4.2.1 Tissue-Derived (Natural) Biomaterials Urinary Bladder Matrix-Derived Biomaterial Small Intestinal Submucosa-Derived Biomaterial Myocardium ECM-Derived Biomaterial 6.4.2.2 Nontissue-Derived (Natural) Biomaterials Chitosan Alginate 6.4.2.3 Purified Proteins Collagen Hydrogels Fibrin 6.4.2.4 Cell-Derived Matrices 6.5 Conclusions References 7: Evolution of Stem Cells in Cardio-Regenerative Therapy 7.1 Introduction 7.2 First Generation 7.2.1 Bone Marrow Stem Cells 7.2.1.1 BM-Derived Stem Cells in Pre-Clinical Cardiovascular Research Bone Marrow Mesenchymal Stem Cells Bone Marrow Progenitor Cells 7.2.1.2 Bone Marrow Mononuclear Cells 7.2.1.3 Bone Marrow-Derived Stem Cells in Cardiovascular Clinical Research Acute Myocardial Infarction Chronic Ischemic Cardiomyopathy Dilated Cardiomyopathy/Heart Failure Mesenchymal Stem Cells 7.2.2 Adipose-Tissue Derived Stem Cells 7.3 Second Generation 7.3.1 Cardiac Stem Cells in Cardiovascular Regeneration 7.3.1.1 Brief History of Cardiac Stem Cells 7.3.1.2 Preclinical Evolution of CSCs in the Repair of Cardiovascular Diseases 7.3.1.3 Clinical Studies Involving CSCs in Cardiovascular Disease 7.3.1.4 Pros and Cons of CSCs 7.3.2 Embryonic Stem Cells 7.3.2.1 Embryonic Stem Cells by the Years 7.3.2.2 ESCs Transplantation and Integration into Host Tissue 7.3.2.3 Preclinical Studies on Cardiovascular Diseases with ESCs 7.3.2.4 Clinical Studies Involving hESCs in Heart Disease 7.3.2.5 Problems with ESCs 7.4 Third Generation 7.4.1 Induced Pluripotent Stem Cells 7.4.1.1 Pre-Clinical Studies on Cardiovascular Diseases with iPSCs 7.4.1.2 Limitations/Shortcomings with the Use of iPSCs 7.4.2 Skeletal Myoblasts 7.4.2.1 Limitations 7.4.3 Endometrial/Menstrual Blood-Derived Stem Cells 7.4.3.1 The Case for Endometrial-Derived Stem Cells 7.5 Exosomes 7.5.1 Pluripotent Stem Cell-Derived Exosomes 7.5.2 Multipotent MSC-Derived Exosomes 7.5.3 Multipotent Cardiac Stem and Progenitor Cell-Derived Exosomes 7.5.4 Advantages of Exosomes Over Traditional Stem Cell Therapies 7.6 Stem Cells as the Future of Cardiovascular Disease Therapy References 8: Stem-Cell-Based Cardiac Regeneration: Is There a Place For Optimism in the Future? 8.1 Introduction 8.2 Stem-Cell-Based Therapy of Failing Heart 8.3 Primary Mechanisms of Action of Cellular Cell Therapy 8.4 Stem Cells in Adverse Cardiac Remodeling 8.4.1 Bone-Marrow-Derived Mononuclear Cells 8.4.2 Mesenchymal Stromal Cells 8.4.3 Cardiac-Derived Stem Cells 8.4.4 Pluripotent Stem Cells 8.5 Stem Cells in Clinical Trials for Patients with Ischemia-Induced Adverse Cardiac Remodeling 8.5.1 Human Allogeneic MSCs 8.5.2 Other Types of Cells 8.6 Ongoing Cell-Based Therapy Clinical Trials Among HF Patients 8.7 Conclusions References 9: Dental Mesenchymal Stem/Progenitor Cells: A New Prospect in Regenerative Medicine 9.1 Introduction 9.2 Types of Dental Mesenchymal Stem/Progenitor Cells 9.2.1 Dental Pulp Stem/Progenitor Cells (DPSCs) 9.2.2 Properties and Differentiation Ability of DPSCs 9.2.3 Immunomodulatory Properties of DPSCs 9.2.4 Regulation of DPSCs’ Behaviors 9.2.5 DPSCs Versus Other MSCs 9.2.6 Preclinical and Clinical Applications of DPSCs 9.3 Stem/Progenitor Cells from Exfoliated Deciduous Teeth (SHEDs) 9.3.1 Properties and Differentiation Ability of SHEDs 9.3.2 Immunomodulatory Properties of SHEDs 9.3.3 Preclinical and Clinical Applications of SHEDs and their Secretome 9.4 Gingival Mesenchymal Stem/Progenitor Cells (GMSCs) 9.4.1 Properties and Differentiation Ability of GMSCs 9.4.2 Immunomodulatory Properties of GMSCs 9.4.3 Preclinical and Clinical Applications of GMSCs and their Secretome 9.5 Periodontal Ligament Stem/Progenitor Cells (PDLSCs) 9.5.1 Differentiation Ability of PDLSCs 9.5.2 Immunomodulatory Properties of PDLSCs 9.5.3 Factors that Regulate the Differentiation and Therapeutic Potential of PDLSCs 9.5.4 Clinical Applications of PDLSCs and their Secretome 9.6 Stem/Progenitor Cells from Apical Dental Papilla (SCAPs) 9.6.1 Immunomodulatory Properties of SCAPs 9.6.2 Differentiation Potential of SCAPs 9.6.3 Potential Application of SCAPs 9.7 Dental Follicle Stem/Progenitor Cells 9.7.1 Immunomodulatory Properties of DFSCs 9.7.2 DFSCs Differentiation Potential 9.7.3 Potential Application of DFSCs 9.8 Limitations Associated with Employing DMSCs in Tissue Regeneration 9.9 Conclusion References 10: Stem Cell-Based Tissue Engineering for Functional Enamel and Dentin/Pulp Complex: A Potential Alternative to the Restorative Therapies 10.1 Introduction 10.2 Cells 10.2.1 Sources of Cells for Dental Tissue Engineering Strategies 10.2.2 Cells Used in Enamel Regeneration (Fig. 10.1 and Table 10.1) 10.2.2.1 Differentiated Cells Differentiated Cells of Dental Origin Differentiated Cells of Nondental Origin 10.2.2.2 Stem/Progenitor Cells Stem/Progenitor Cells of Dental Origin Stem/Progenitor Cells of Nondental Origin 10.2.3 Cells Used in Dentin–Pulp Complex Regeneration (Fig. 10.1 and Table 10.1) 10.2.3.1 Stem/Progenitor Cells Stem/Progenitor Cells of Dental Origin Stem/Progenitor Cells Derived from Human Adult Teeth Stem/Progenitor Cells Derived from Developing Teeth Induced Pluripotent Stem Cells Stem/Progenitor Cells of Nondental Origin 10.3 Scaffolds 10.3.1 Definition 10.3.2 Natural Sources 10.3.3 Synthetic Sources 10.4 Requirements of an Ideal Scaffold 10.4.1 Porosity 10.4.2 Mechanical Properties 10.4.3 Biocompatibility 10.4.4 Immune Acceptance 10.5 Scaffolds Used in Enamel Regeneration (Fig. 10.2 and Table 10.1) 10.5.1 Synthetic Enamel Fabrication: Regenerating Enamel-Like Hydroxyapatite Microstructures 10.5.2 Enamel Regeneration via Cell-Based Strategies: Regenerative Treatment Requires Stem Cells, Scaffold, and Growth Factors 10.6 Scaffolds and Biodegradable Materials for Dentin and Pulp Regeneration (Fig. 10.2 and Table 10.1) 10.7 Signaling Molecules 10.7.1 Importance of Growth Factors and Signaling Molecules in Dental Regeneration 10.7.2 Signaling Molecules Used in Enamel Regeneration (Fig. 10.3 and Table 10.1) 10.7.3 Signaling Molecules Used in Dentin Regeneration (Fig. 10.3 and Table 10.1) 10.7.4 Signaling Molecules Used in Pulp Regeneration (Fig. 10.3 and Table 10.1) 10.8 Conclusion References 11: Cell- and Stem Cell-Based Therapies for Liver Defects: Recent Advances and Future Strategies 11.1 Introduction 11.1.1 The Liver Is a Key Organ with an Astonishing Ability of Regeneration 11.1.2 Treatment of Liver Diseases Remains a Wide Unmet Medical Need for Both Medical and Patient Communities 11.2 Liver Cell Transplantation Is a New Therapeutic Modality Initially Designed to Substitute OLT 11.3 Lessons from Clinical Hepatocyte Transplantation Trial Cases 11.4 Stem Cells Are Developed as Second-Generation Cell Products for Liver 11.4.1 Regenerative Medicine 11.5 Extrahepatic Stem Cells 11.5.1 Hematopoietic Stem Cells 11.5.2 Pluripotent Stem Cells 11.5.3 Mesenchymal Stem Cells 11.6 Liver Stem Cells 11.6.1 Endogenous Stem Cells 11.6.2 Still Intrinsically Non-defined Stem/Progenitor Cells 11.7 Regulatory Framework 11.8 Concluding Remarks References 12: Stem Cells: A Renewable Source of Pancreatic β-Cells and Future for Diabetes Treatment 12.1 Introduction 12.2 Diabetes and Stem Cell Function 12.2.1 Hyperglycemia Alters Stem/Progenitor Cell Morphology and Surface Marker Expression 12.2.2 Hyperglycemia Affects Stem/Progenitor Cell Mobilization 12.2.3 Hyperglycemia Modulates the Paracrine Activity of Stem/Progenitor Cells 12.3 Stem Cell Therapy and Diabetes 12.3.1 Cell-Based Therapy in Regenerative Medicine 12.3.2 Stem Cell-Based Therapy and Diabetes 12.3.3 Using Stem Cells as Magic Bullets to Cure Diabetes 12.4 Stem Cells Reprogramming to Insulin-Secreting β-Cells 12.5 Pluripotent Stem Cells for β-Cell Regeneration 12.5.1 ESCs as a Renewable Source of β-Cells 12.5.2 iPSCs as a Renewable Source of β-Cells 12.6 Development of Direct Reprogramming Protocol Using miRNA Approach 12.6.1 Advances in Insulin-Producing Cells for iPSCs and Future Perspective References 13: Induced Pluripotent Stem Cells in Pediatric Research and Clinical Translation 13.1 Introductıon 13.2 Stem Cell Research and Clinical Use in Pediatrics 13.2.1 Stem Cell Experience in Pediatrics Toward iPSCs 13.3 Increased Incidence of Inherited Diseases in Childhood 13.3.1 Disease Modeling and Drug R&D with iPSCs 13.4 Limited Amount of Biological Samples in Pediatrics 13.5 Increased Regenerative Potential of Children and Future Use of iPSCs in Clinics 13.6 Congenital Anomalies, Birth Complications, and Availability of  Umbilical Cord Stem Cells 13.6.1 Future Use of Cord Blood for iPSC Generation 13.7 Gene Therapy Applications: iPSCs and CRISPR-Cas9 Gene Editing 13.8 Adverse Drug Reactions in Children: Personalized Therapy with iPSCs 13.9 Regulations in Pediatric Clinical Research 13.10 Technical Issues and Need for iPSCs Banking: For Research and Clinic 13.10.1 Generation and Characterization of iPSCs 13.10.2 Banking of iPSCs 13.11 Further Developments in the iPSCs Field 13.11.1 Disease Modeling and the Next-Generation Technologies with iPSCs 13.11.2 Organoid Research with iPSCs: A Step Toward Organoid Medicine 13.11.3 Drug Repurposing/Repositioning with iPSCs for Fast-Track Clinical Trials 13.11.4 Clinical Use of iPSCs in Regenerative Medicine 13.12 Future Perspective and Conclusions References 14: Maturity of Pluripotent Stem Cell-Derived Cardiomyocytes and Future Perspectives for Regenerative Medicine 14.1 Introduction 14.2 Difference Between the Characteristics of Immature and Mature Cardiomyocytes 14.2.1 Morphology 14.2.2 Contractile Apparatus 14.2.3 Calcium Handling 14.2.4 Electrophysiology 14.2.5 Cell Cycle 14.2.6 Metabolism 14.3 Current Maturation Strategies 14.3.1 Prolonged Culture 14.3.2 Extracellular Matrices (ECMs) 14.3.3 Hormonal Treatments 14.3.4 Alternations of Energy Source 14.3.5 Substrate Stiffness 14.3.6 Electrical Stimulation 14.3.7 Co-culture with Non-cardiomyocytes 14.3.8 In Vivo Maturation 14.3.9 3D Culture System 14.4 Future Perspectives of PSC-CMs 14.4.1 Cardiac Disease Modeling 14.4.2 Pharmacological Studies 14.4.3 Cell Transplantations 14.5 Conclusion References 15: Availability of Pluripotent Stem Cells from Normal Cells in Cancer Science 15.1 Introduction and a Short History of Cancer Research 15.2 Cancer Stem Cells in Cancer Science 15.3 Utilizing iPSC in Cancer Science 15.4 Investigation of Tumor Initiation Mechanisms with iPSCs 15.5 Using iPSCs-Derived CSCs to Study Cancer Microenvironment and Heterogeneity 15.6 Drug Screening, Precision Medicine, and New Treatment Strategies 15.7 Current Challenges and Future Perspectives References Index