Biology of Stem Cells and the Molecular Basis of the Stem State (eBook)

Preface 6
Contents 8
Prologue: Stemness as an Indispensable Biological Trait of Multicellular Organisms 15
Chapter Summaries 19
Chapter Summaries 19
Chapter 1: Historical Roots 19
Chapter 2: Multipotency and Tissue-Specific Stem Cells 19
Chapter 3: Stem Cells with No Tissue Specificity 19
Chapter 4: Stem Cell Niches 20
Chapter 5: A Critical Analysis of Properties Commonly Ascribed to Stem Cells 20
Chapter 6: The Stem State: Stemness as a State in the Cells Life Cycle 20
Chapter 7: The Stem State in Cancer 21
Chapter 8: MSC Therapy in Animal Models and in Regenerative Medicine for Human Diseases 21
1 Historical Roots 22
1.1 The Stem Cell Notion: Is There a Stem Cell for Each and Every Hemopoietic Cell Type? 22
1.2 The Emergence of Bone Marrow Transplantation 24
1.3 The Origin of Contemporary Notions on Stem Cells 27
1.3.1 The HSC 27
1.3.2 The Immediate Descendants of HSCs: In Vitro Demonstration of Committed Progenitor Cells 31
1.3.3 Colony-Stimulating Factors and the Emergence of the Cytokine Notion 33
1.3.4 Further Insights into the Structure of the Hemopoietic Hierarchy and the Nature of Cells Within the Hemopoietic Cascade 34
1.3.5 The Stem Cell is Not Solitary: The Hemopoietic Stem Cell Niche 38
1.3.5.1 The Hemopoietic Inductive Microenvironments 38
1.3.5.2 Cytokines are Pleiotropic and Redundant 40
1.3.5.3 The Control of Hemopoiesis may not be Achieved by Simple Feedback Regulation 41
1.3.5.4 The Hemopoietic Stem Cell Niche Within the Bone Marrow Microenvironment 43
1.3.5.5 Antagonism with Differentiation Leads to Stem Cell Renewal 46
1.3.5.6 The Restrictive Nature of Hemopoietic Microenvironments 48
1.4 Conclusions, Questions, and Enigmas 49
1.5 Box 1.1 The definition of stemness-Stage I 50
References 52
2 Multipotency and Tissue-Specific Stem Cells 60
2.1 Tissue-Specific Stem Cells from Organs Capable of Extensive Regeneration 60
2.1.1 HSCs Versus Other Tissue-Specific Stem Cells 60
2.1.2 Liver Progenitor Cells 61
2.2 Tissue-Specific Stem Cells from Organs Undergoing Extensive Repopulation and Repair 63
2.2.1 Skin Stem Cells 63
2.2.2 Gut Stem Cells 67
2.3 Tissue-Specific Stem Cells in Tissues and Organs Exhibiting Moderate Repopulation and Repair Capabilities 68
2.3.1 Skeletal Muscle Stem Cells 69
2.3.2 Cardiovascular Progenitor Cells 70
2.4 Tissue-Specific Stem Cells in Tissues and Organs Exhibiting Poor Regeneration and Repair Capabilities 70
2.5 Conclusions, Questions, and Enigmas 71
References 74
3 Stem Cells with No Tissue Specificity 77
3.1 Mesenchymal Cells: A Body-Wide Distributed Population that Includes Multipotent Cells 77
3.1.1 MSC Isolation 83
3.1.2 Growth, Senescence, and Tumorigenicity 85
3.1.3 Tissue and Organ Distribution 86
3.1.4 The Antigenic Phenotype of MSCs 87
3.1.5 Hierarchy 91
3.1.6 MSC Transplantation and Homing 93
3.1.7 Migratory Properties of MSCs 96
3.1.8 Molecular Basis of MSC Growth and Differentiation Control 97
3.1.9 Hemopoietic Supportive Capacity of MSCs 99
3.1.10 Immunoregulatory Functions of MSCs 99
3.1.11 Other Members of Mesenchymal Tissues? 101
3.2 Adult Pluripotent Stem Cells 101
3.3 The Case of ESCs 104
3.4 Conclusions, Questions, and Enigmas 108
3.4.1 Verifying Multipotency of MSCs by Single Cell Experiments 108
3.4.2 Do MAPCs and Similar Adult Cells Differentiate into the Three Germ Layers? 109
3.4.3 Not All that Grows Fast is a Stem Cell: The Opposite may be the Case 109
3.4.4 Who are the In Vivo Counterparts, or Precursors, of MSCs, MAPCs and Cells Alike, and Which are the Molecules that Control These Cells In Vivo? 109
3.4.5 What are the MSC Molecules that Mediate T Cell Suppression, and Why do Different Studies Reach Different Conclusions? 110
3.4.6 Reservations Regarding In Vitro MSC Migration Assays 110
3.4.7 Segregation of Stem Cells into Types Based on Differentiation Potency and Organ Distribution 111
3.4.8 Is the Relative Capacity of Organs to Repopulate and Regenerate, Dependent Upon the Incidence or Potency of the Tissue Non-Specific Stem Cell? 112
3.4.9 Embryogenesis Versus Adulthood: Cellular Plasticity Versus Stem Cells 113
3.4.10 The Relatively Autonomous Nature of Mesenchyme 113
References 114
4 Stem Cell Niches 129
4.1 Universality of the Stem Cell Niche Concept: From Plants to Mammalians 129
4.1.1 Plants and Worms 129
4.1.2 Drosophila Gonads 129
4.1.3 Mammalian Male Gonads 131
4.1.4 Mammalian Hair Follicle Melanocytes 132
4.1.5 Mammalian Neuronal Cells 132
4.2 The Cellular and Molecular Structure of Stem Cell Niches 133
4.2.1 Drosophila Gonadal Niche 133
4.2.2 The HSC Bone Marrow Niche 135
4.2.2.1 The Role of the Endothelium in the Processes of HSC Homing and Engraftment into the Bone Marrow 136
4.2.2.2 The Contribution of Endosteum-Lining Cells to the Formation the HSC Niche 137
4.2.2.3 The Contribution of Perivascular Sites to the Formation of HSC Niches 140
4.2.2.4 Contribution of Subendothelial-Region Cells in the Bone Marrow Stroma 141
4.2.2.5 Anchoring of HSCs to Their Niches 141
4.2.2.6 Molecular Signaling Controlling HSC in Their Niches 142
4.2.2.7 In Vitro Simulations of HSC Niches 143
4.2.2.8 A Critical View of Current Knowledge Regarding the Structure and Function of the HSC Niche 144
4.2.3 The Epithelial Stem Cell Niche 145
4.2.4 Mammalian Neuronal Cell Niches 145
4.2.5 Intestinal Niche 145
4.3 Studies on Mammalian Stem Cell Self-Renewal: Relevance to the Niche 145
4.4 The Molecular Basis of Asymmetrical Divisions 148
4.5 Homeless Orphans: Stem Cells with Unknown Niches 149
4.5.1 Do Migratory Pathways of Adult Stem Cells Reveal Their Niches? 149
4.5.2 MSCs, MAPCs, and ESCs Do Not HaveWell-Characterized Niches 153
4.6 Conclusions, Questions, and Enigmas 154
4.6.1 Cell Attraction to Their Niches: A Noteon Chemokine Gradients 154
4.6.2 Do Different Types of Stem Cells Exist, Some Niche--Dependent and Others Niche--Independent? 155
4.6.3 ''We Murder to Dissect'' (from William Wordsworth (1770''1850) ''The Table Turned'') 156
4.6.4 Tissue Microenvironments Versus Stem Cell Renewal Niches 158
4.6.5 The Chicken and the Egg: Does the Niche Dictatethe Formation of the Stem Cell or Does the Stem CellInstruct the Formation of the Niche? 159
4.6.6 Are There Niches for Multi/Pluripotency? 159
References 160
5 A Critical Analysis of Properties Commonly Ascribed to Stem Cells 171
5.1 Stem Cell Definitions Vary 171
5.2 Specific Markers 171
5.2.1 The Gene Expression Pattern of Stem Cells: Are There Stemness Genes? 172
5.2.1.1 Cell Surface Markers and Gene Expression Profiles 172
5.2.1.2 Signaling Pathways 174
5.3 In Vitro Versus In Vivo 175
5.4 The Issue of Rareness 176
5.5 The Undifferentiated State: Is Any Cell that Precedes the Other Within the Differentiation Cascade, a Stem Cell? 176
5.6 Quiescence 177
5.7 Self-Renewal 177
5.8 Indefinite Renewal 181
5.9 Extensive Proliferation 182
5.10 Niche Dependence 183
5.11 Symmetric Versus Asymmetric Divisions 183
5.12 Robust Regeneration and Reconstitution of Tissues 184
5.13 Migration and Homing 184
5.14 Differentiation Capacity 185
5.15 Multipotency and Pluripotency 186
5.16 Conclusions 188
References 190
6 The Stem State: Stemness as a State in the Cells Life Cycle 196
6.1 The Stem Cell Versus the Stem State 196
6.2 The Molecular Basis of Stemness: A Specific Gene Expression Pattern Versus Epigenetic Modulations 197
6.3 Dedifferentiation 200
6.3.1 Plant Cells 200
6.3.2 Germ Cells in Insects and Mammalians 200
6.3.3 Regeneration of Whole Organs in Urodeles 202
6.3.4 Mammalian Muscle 203
6.3.5 Mammalian Nerve Cells 204
6.3.6 Mammalian Melanocytes 204
6.3.7 Mammalian Adipocytes 204
6.3.8 Mammalian Pancreatic Cells 205
6.3.9 Normal and Tumor Mammalian Hemopoietic Cells 206
6.3.10 Reversed Differentiation in Adult Tissue and During Development 206
6.4 Transdifferentiation 206
6.4.1 Bone Marrow Cells Participate in the Repair and Repopulation of Non-Hemopoietic Tissues 207
6.4.2 Do HSCs Differentiate into Non-Hemopoietic Cells? 208
6.4.3 Mesenchymal Progenitors from the Bone Marrow and Other Body Sites Differentiate into Non-Mesodermal Derivatives 209
6.4.4 Transdifferentiation of Various Adult Tissue Cells 210
6.4.5 Fusion-Induced Reprogramming and Transdifferentiation 211
6.5 Reprogramming by Enforcing Dedifferentiation and Transdifferentiation Artificially 212
6.5.1 Nuclear Transfer 212
6.5.2 Reprogramming and Lineage Transitions by Enforced Expression of Transcription Factors 215
6.5.3 From Mature Cells Back to ESC-Like Cells: Induced Pluripotent Cells 216
6.5.4 Generation of Induced Pluripotent Cells from Mature B Lymphocytes 217
6.5.5 Reprogramming by Cell Extracts 218
6.5.6 Spontaneous Reprogramming Under Culture Conditions: Reprogramming Does Not Necessarily Require Enforced Introduction of Exogenous Molecules into Cells 218
6.6 The Stem State 219
6.6.1 (Panta rhey-Everything is in a State of Flux) in Reference to the Thoughts of Heraclitus, 535--475 BCE)
6.6.2 Many Avenues to Pluripotency, But Only One Underlying Mechanism 220
6.7 Conclusions, Questions, and Enigmas 222
6.7.1 The Molecular Signature of the Stem State 222
6.7.2 Dedifferentiation, Transdifferentiation, and Plasticity: How Do They Relate? 223
6.7.3 Controversies Over the Issue of Mammalian Cell Plasticity 224
6.7.4 Where Have All the Stem Cells Gone? 224
6.7.5 The Stem State and the Niche 225
References 225
7 The Stem State in Cancer 236
7.1 Tumorigenesis and Tumor Growth 236
7.2 The Tumor-Initiating Cell 239
7.3 Tumor Stem Cells 240
7.4 Inconsistencies and Contradictions Within the Tumor Stem Cell Theory 243
7.4.1 Defining Tumor Stem Cells Solely on Grounds of Tumor-Forming Capacity 244
7.4.2 Reductionist Definitions 245
7.4.3 Tying Up Self-Renewal and Indefinite Proliferation 246
7.4.4 Differentiating Cells Acquire ''Stemness'' 247
7.4.5 Tying Up Tumor Origin and Tumor Mass Maintenance 248
7.4.6 Cells Within Tumors Are, At Most, Oligopotent 249
7.5 TICs are Biologically Distinct from Stem Cells: The TIC Does Not Possess Any of the Major Traits of Normal Stem Cells 250
7.6 Tumors are Stem Cell--Deficient 251
7.7 Conclusions and Enigmas 257
References 258
8 MSC Therapy in Animal Models and in Regenerative Medicine for Human Diseases 264
8.1 Progenitor Cell Therapy: General Considerations 264
8.2 BMT: Transplantation of Unmanipulated Cells, Shortly After Their Isolation 267
8.3 Transplantation of Ex Vivo Propagated MSCs as a Therapy Modality 269
8.3.1 General Considerations and Possible Hurdles 269
8.3.2 MSCs in Animal Models 269
8.3.2.1 MSCs in Tumors 269
8.3.2.2 Tissue Repair Following MSC Infusion 271
8.3.3 MSCs in Human Disease 274
8.4 Transplantation of Ex Vivo Propagated, Genetically Manipulated Cells 275
8.5 Ex Vivo and In Vivo Engineering of Complete Tissues and Organs 276
8.6 Future Prospects: The Awakening of Resident Stem Cells 278
References 279
References 288
Index 289