Stem Cell Biology in Health and Disease

Preface

Contents

Contributors

1 Introduction

References

Part I Bone Marrow-Derived Stem Cells

2 Hematopoietic Stem and Progenitor Cells in Clinical Use Transplantation and Mobilization

2.1 Historical Aspects

2.2 Stem Cell Donors

2.3 Stem Cell Mobilization and Autologous Transplantation

2.4 Allogeneic Transplantation

2.5 Outlook

References

3 Ex Vivo Expansion of HSPCs

3.1 The Sources of HSPCs

3.1.1 Bone Marrow HSPCs

3.1.2 Peripheral HSPCs

3.1.3 Umbilical Cord Blood HSPCs

3.2 The Expansion of HSPCs

3.2.1 Cytokines

3.2.2 Ex Vivo Expansion of HSPCs

3.2.3 Regulation of HSPCs Expansion

3.2.4 Free Radical Regulation on HSPCs Expansion

3.2.5 Megakaryocytic Progenitor Cells Expansion

3.2.6 Red Cells Expansion

3.2.7 T-Cell Expansion

3.2.8 NK Cell Expansion

3.2.9 DC Expansion

3.2.10 HSPC Ex Vivo Expansion and Gene Therapy

3.3 Expansion Bioreactor

3.4 The Application of Expanded HSPCs

3.4.1 Transplantation of HSPCs in Animal Model

3.4.2 Transplantation of HSPCs in Human

3.5 The Future of HSPCs Expansion

References

4 Modulation of Hematopoietic Stem/Progenitor Cell Migration

4.1 Introduction

4.2 The SDF-1/CXCR4 Axis

4.2.1 Stromal Cell-Derived Factor-1 (SDF-1)

4.2.2 CXCR4

4.2.3 SDF-1/CXCR4 Signaling

4.3 Homing of HSPCs to Bone Marrow and Organs

4.4 Influence of Culture Conditions on the Migration of Human CD34+/CD133+ Cord Blood HSPCs

4.5 Influence of Culture Conditions on the Migration of Murine Lin- c-kit+ HSPCs

4.6 Termination of the SDF-1 Induced Migration of HSPCs

4.7 Conclusion

References

5 Properties of Mesenchymal Stem Cells to Consider for Cancer Cell Therapy

5.1 Identifying MSCs

5.2 Tissue Origin of MSCs

5.3 Induced Pluripotent Stem Cells and MSCs

5.4 MSC Homing in Tissue Repair and Oncogenesis

5.5 MSCs Tumor Tropism and Pro-metastatic Effects

5.6 Chemokine Receptors Regulating MSCs Homing

5.7 Growth Factor Receptors Regulating MSCs Homing

5.8 Toll-Like Receptors and Death Receptors in MSC Migration

5.9 Oncogenic Potential of MSCs

5.10 Immunosuppressive Effects of MSCs

5.10.1 T Cells

5.10.2 NK Cells

5.10.3 DCs

5.10.4 B Cells

5.11 Modulation of MSCs Immunosuppression

5.12 MSCs for Cellular Gene Therapy

5.13 Retroviral Vectors for MSC Gene Transfer

5.14 Electroporation for MSC Gene Transfer

5.15 Ex Vivo Reprogramming of MSCs Without Gene Transfer

5.16 Cytokine-Producing MSCs for Cancer Cell Therapy

5.17 Oncolytic Virus-Infected MSCs

5.18 Conclusion

References

Part II Embryonic Stem Cells

6 Alternative Embryonic Stem Cell Sources

6.1 Introduction

6.2 Embryonal Carcinoma (EC) Cells

6.3 Embryonic Stem (ES) Cells

6.3.1 Hallmarks of ES Cells

6.3.2 Regulation of Self-Renewal and Pluripotency of ES Cells

6.3.2.1 Extrinsic Factors

6.3.2.2 Transcriptional Regulation

6.3.2.3 Epigenetic Regulation

6.3.2.4 MicroRNAs

6.4 Alternative Sources of Pluripotent Stem Cells

6.4.1 Derivation of Pluripotent Stem Cells by Reprogramming of a Somatic Nucleus

6.4.1.1 Somatic Cell Nuclear Transfer (SCNT)

6.4.1.2 Cytoplasmic Hybrids

6.4.1.3 Altered Nuclear Transfer (ANT)

6.4.1.4 Nuclear Reprogramming by Cell Fusion

6.4.1.5 Nuclear Reprogramming by Cell Extracts

6.4.1.6 Nuclear Reprogramming by Defined Transcription Factors

6.4.1.7 Alternative Ways for Obtaining Pluripotent Stem Cells from Early Embryos

6.4.2 Pluripotent Stem Cells Derived from Germ Cells

6.4.2.1 Pluripotent Stem Cells from Testis

6.4.2.2 Pluripotent Stem Cells from Oocytes

6.5 Future Prospects and Conclusions

References

7 Cell Therapy in Parkinsons Disease

7.1 Introduction

7.2 Fetal Ventral Mesencephalon

7.3 Fetal Neural Precursor Cells

7.4 Embryonic Stem Cells

7.5 Induced Pluripotent Stem Cells (iPS Cells)

7.6 Adult Stem Cells

7.7 Conclusions

References

8 Transplantation of Stem Cells and Their Derivatives in the Treatment of Multiple Sclerosis

8.1 Introduction

8.2 The Pathology of Multiple Sclerosis

8.3 Current Treatments for Multiple Sclerosis

8.4 The Need for Repair-Oriented Therapies for Multiple Sclerosis

8.4.1 Transplantation of Exogenous Stem Cells

8.4.2 Mobilization of Endogenous Stem Cells

8.5 Which Exogenous Stem Cells Can Be Used for Transplantation?

8.5.1 Embryonic Stem Cells

8.5.2 Induced Pluripotent Stem Cells

8.5.3 Neural Stem Cells

8.5.4 Hematopoietic Stem Cells (HSCs) and Mesenchymal Stem Cells (MSCs)

8.6 Stem Cells and Stem Cell-Derived Precursors are Capable of Myelination in Animal Models

8.6.1 Remyelination in Genetic Disease Models

8.6.2 Remyelination Following Chemically-Induced Demyelination

8.7 Studies of Stem Cells in Experimental Autoimmune Encephalomyelitis Models

8.7.1 Survival and Migration of Stem Cell-Derived Progenitors in EAE

8.7.2 Immunomodulatory Effects of Stem Cell-Derived Progenitors in EAE

8.7.3 Remyelination by Stem Cell-Derived Progenitors in EAE

8.8 Initial Investigations into Exogenous Cell-Based Therapy in Multiple Sclerosis

8.9 Future Directions

8.9.1 Establishing the Myelinating Capacity of Stem Cells in MS

8.9.2 Inflammation and Astrocytes

8.9.3 Method of Cell Delivery to MS Patients

8.9.4 The Use of Genetically Modified Cells for Transplantation

8.9.5 Selection of MS Patients for Transplantation Therapy

References

Part III Cancer Stem Cells

9 Cancer: A Stem Cell-based Disease?

9.1 Introduction

9.2 Evolution of Homeostatic Control of the Hierarchical and Cybernetic Nature of Human Health

9.3 The Concept of Stem Cells in the Evolutionary Transition from Single Cell Organisms and the Metazoan

9.4 Gap Junctional Intercellular Communication as the Evolutionary Biological Rosetta Stone for Understanding the Homeostatic Regulation of Cellular Functions in Metazoans

9.5 Cancer as the Result of a Disease of Homeostatic Control of Cell Communication

9.6 Role of Gap Junctions in the Multi-Stage/Multi-Mechanism Hypothesis of Carcinogenesis

9.7 What Is Source of the Initiated Cell?

9.8 Adult Stem Cells, Immortalizing Viruses and Cancers:

9.9 Tumors and Tumor Cell Lines: A Mixture of Cancer Stem Cells and Cancer Non-stem Cells

9.10 Characteristics of Normal Adult Stem Cells, Cancer Stem Cells and Cancer Non-stem Cells

9.11 Cancer Stem Cells, Drug-Resistant Cancer Cells and Side-Population Cells

9.12 Two Types of Cancer Cells

9.13 Stem Cells, Hypoxia, Drug Resistance and Oct-4 A

9.14 Dietary Modulation of Cancer: The Barker Hypothesis, Stem Cell Frequency and Risk to Cancer

9.15 Does the Adult Stem Cell or the Differentiated Somatic Cell Act as the Target Cell for the Initiation of Cancer

9.16 Conclusion

References

10 Stem Cell Niche Versus Cancer Stem Cell Niche Differences and Similarities

10.1 Introduction

10.2 The Stem Cell Niche in Normal Tissue

10.3 The Inflammatory Niche

10.4 The Immunological Niche

10.5 The Tumor Cell Niche

10.6 Conclusion

References

11 The Chronically Inflamed Microenvironment and Cancer Stem Cells

11.1 Introduction

11.2 The Association of Inflammation and Cancer

11.3 What Does the Chronic Inflammatory Environment Look Like?

11.4 What are the Long Term Effects of Chronic Inflammation?

11.5 Inflammation and Tumors Inflammations Many Roles

11.6 Summary

References

12 Does the Chronically Inflamed Periodontium Harbour Cancer Stem Cells?

12.1 Introduction

12.2 Stem Cells and Periodontal Tissue Regeneration

12.3 Animal Models in Periodontal Research

12.4 Tumor Induction Mediated by pdSCs?

12.5 Discussion

12.5.1 Stem Cells in the Periodontium

12.5.2 The Periodontal Defect

12.5.3 Source of pdSCs

12.5.4 Special Features

12.5.5 Considering the Nude Rats

12.5.6 pdSCs and Tumor Initiation

12.6 Conclusion

12.6.1 Periodontal Stem Cells as Functional Elements of Regenerative Periodontology

12.6.2 Possible Periodontal Tissue Regeneration

References

13 Leukemia Stem Cells

13.1 Introduction

13.2 Stem cells in acute myeloid leukemia are defined by their ability to reconstitute leukemia in serially transplanted NOD/SCID mice

13.3 Phenotype of Leukemia Stem Cells in AML

13.4 Leukemia Stem Cells in CML

13.5 Stem Cells in Acute Lymphoblastic Leukemia (ALL)

13.6 Identity of Leukemia Stem Cells in ALL Is Controversial

13.7 Leukemia Stem Cells and Drug-Resistance in ALL

13.8 Mechanisms of Leukemia Stem Cell Self-renewal

13.8.1 The PTEN/PI3K/AKT/FOXO Axis

13.8.2 Deregulation of CDX2/HOX Genes

13.8.3 Nuclear Reprogramming by OCT4

13.8.4 WNT/ -Catenin Signaling Pathway

13.9 Perspective

References

14 Cancer Stem Cells in Solid Tumors

14.1 Introduction

14.2 Finding the Needle in the Haystack: Identifying Phenotypically Distinct Prospective Cancer Stem Cells

14.2.1 Sphere Assays

14.2.2 Side Population Cells

14.2.3 Cancer Stem Cell Markers

14.2.3.1 Brain

14.2.3.2 Breast

14.2.3.3 Colon

14.2.3.4 Head and Neck

14.2.3.5 Kidney

14.2.3.6 Liver

14.2.3.7 Ovary

14.2.3.8 Pancreas

14.2.3.9 Prostate

14.2.3.10 Skin

14.3 Cell of Origin of Cancer Stem Cells

14.4 Perspectives and Challenges

References

15 One for All or All for One? The Necessity of Cancer Stem Cell Diversity in Metastasis Formation and Cancer Relapse

15.1 Introduction

15.2 The Necessity of Different CSC Subtypes

15.3 The Origin of Primary Tumor CSCs

15.3.1 Do pCSCs Originate from Adult Stem Cells?

15.3.2 Do pCSCs Originate from Progenitor Cells?

15.3.3 Do pCSCs Originate from Cell Fusion Events?

15.4 Metastatic CSCs

15.4.1 The Origin of Metastatic CSCs

15.4.1.1 Cell Fusion and Metastatic CSCs

15.4.2 Do Organ-Specific Gene Signatures Point to the Existence of Organ-Specific mCSCs?

15.5 Cancer Relapse and CSCs

15.5.1 Oncogenic Resistance and Recurrence CSCs (rCSCs)

15.5.2 How Do rCSCs Originate?

15.5.3 Cell Fusion and rCSCs

15.6 Conclusions

References

16 Elimination of Cancer Stem Cells

16.1 The Cancer Stem Cell Hypothesis

16.2 The Failure of Conventional Cancer Therapies

16.3 Searching for a Valid Target: Knowledge of Stem Cell Biology

16.3.1 Self-renewal

16.3.2 Differentiation Potential

16.3.3 Quiescence/Long-Life

16.3.4 Metastasis

16.3.5 Migration

16.3.6 Transplantation

16.4 Therapeutic Approaches Against Cancer Stem Cells: Eliminating CSCs

16.4.1 Differentiation Therapies

16.4.2 Destruction Therapies

16.4.2.1 Targeted Therapy Against Self-renewal Signaling Pathways

16.4.2.2 Modulation of Chemoresistance Mechanisms

16.4.2.3 Others Mechanism Affecting CSCs or Their Niche

16.5 Imaging CSCs

16.6 Future Prospects

References

17 Potential Molecular Therapeutic Targets in Cancer Stem/Progenitor Cells: Are ATP-Binding Cassette Membrane Transporters Appropriate Targets to Eliminate Cancer-Initiating Cells?

17.1 Introduction

17.2 Phenotypic and Functional Properties of Cancer Stem/Progenitor Cells

17.3 Intrinsic Properties Associated with the Treatment Resistance of Cancer Stem/Progenitor Cells

17.3.1 Structures of ABC Transporters and Their Functions in Multidrug Resistance

17.3.2 Therapeutic Strategies for Overcoming ABC Transporter-Mediated MDR

17.3.2.1 Inhibitors of ABC Transporters

17.3.2.2 Modulatory Agents of the Transduction Signaling Elements Involved in the Regulation of ABC Transporter Expression and Functions

17.4 Implications of Cancer Stem/Progenitor Cells in Cancer Development, Treatment Resistance and Potential Molecular Therapeutic Targets

17.4.1 Functions of Leukemic Stem/Progenitor Cells in Leukemias and Potential Therapeutic Targets

17.4.1.1 Molecular Therapeutic Targets in AML and APL

17.4.1.2 Molecular Therapeutic Targets in CML

17.4.1.3 Stem Cell-Based Transplantation Therapies

17.4.2 Functions of Melanoma Stem Cells in Cutaneous Melanoma and Potential Therapeutic Targets

17.4.3 Functions of Brain Tumor Stem Cells in Brain Cancers and Potential Therapeutic Targets

17.4.4 Functions of Tumorigenic Stem/Progenitor Cells in Epithelial Cancers and Potential Therapeutic Targets

17.4.4.1 New Therapies Against Epithelial Cancers by Molecular Targeting of Tumorigenic and Migrating Cancer Stem/Progenitor Cells and Their Progenies

17.5 Conclusions and Perspectives

References

Index