The Cell Biology of Stem Cells (eBook)

Eran Mes horer, PhD, is studying chromatin plasticity in embryonic and neuronal stem cells at the Department of Genetics at the Hebrew University of Jerusalem. He received his PhD in Molecular Neuroscience from the Hebrew University and conducted his post‑doctoral studies at the National Cancer Institute, NIH. His lab focuses on understanding pluripotency, differentiation and reprogramming from a chromatin perspective, taking both genome‑wide and single cell approaches. He is a member of the International Society for Stem Cell Research and holds the Joseph H. and Belle R. Braun Senior Lectureship in Life Sciences. Kathrin Plath, PhD, is an Assistant Professor in the Department of Biological Chemistry at the University of California Los Angeles since 2004. After she received her PhD from the Humboldt University at Berlin in Germany, she was at the University of California San Francisco and the Whitehead Institute in Cambridge, MA for her postdoctoral studies. Dr. Plath’s main research interest is to understand how developmental cues induce changes in chromatin structure at the molecular level, and how these changes regulate cell fate decisions and gene expression in mammalian development. She is a member of the International Society for Stem Cell Research and of the editorial board of several stem cell journals.

Title page 3
Copyright page 4
PREFACE 5
ABOUT THE EDITORS... 8
ABOUT THE EDITORS... 9
PARTICIPANTS 10
Table of contents 13
CHAPTER 1 EARLY EMBRYONIC CELL FATE DECISIONS IN THE MOUSE 17
Abstract: 17
INTRODUCTION 17
LINEAGE ESTABLISHMENT AND THE PRE-STEM CELL PROGRAM:FORMATION OF THE BLASTOCYST 18
LINEAGE MAINTENANCE AND THE STEM CELL PROGRAM: BEYOND THE BLASTOCYST 22
THE SECOND LINEAGE DECISION: SUBDIVIDING THE ICM 22
CELL SIGNALING REGULATES PE/EPI SPECIFICATION 23
ESTABLISHMENT AND MODULATION OF PLURIPOTENCYIN THE EPI LINEAGE 25
CONCLUSION 26
REFERENCES 27
CHAPTER 2 NUCLEAR ARCHITECTURE IN STEM CELLS 30
Abstract: 30
INTRODUCTION 30
FUNCTIONAL COMPARTMENTALIZATION OF THE ES CELL NUCLEUS 31
Organization of Chromosomes and Single Genes within the Nuclear Space 31
Lamina and the Nuclear Periphery 33
STEM CELL FEATURES OF OTHER NUCLEOPLASMIC SUBCOMPARTMENTS 35
Splicing Speckles and Cajal Bodies 35
Promyelocytic Leukemia Bodies 35
Polycomb Bodies 36
CHROMATIN FEATURES CHARACTERISTIC OF ES CELL NUCLEI 36
Hypermobility of Architectural Chromatin Proteins and Heterochromatin Formation 36
Hypertranscription and DNA Replication in ES Cells 37
Silencing Mechanisms at Developmental Regulator Genes 38
CONCLUSION 38
ACKNOWLEDGEMENTS 38
REFERENCES 39
CHAPTER 3 EPIGENETIC REGULATION OF PLURIPOTENCY 42
Abstract: 42
INTRODUCTION 42
EPIGENETIC MODIFICATIONS 44
Modulators of Chromatin Structure and Dynamics 45
Histone Modifications 45
DNA Methylation 46
THE EPIGENOME OF ES CELLS 47
Chromatin Structure and Dynamics 47
Histone Modifications 48
DNA Methylation 51
CONCLUSION 52
ACKNOWLEDGEMENTS 53
REFERENCES 53
CHAPTER 4 AUTOSOMAL LYONIZATION OF REPLICATION DOMAINS DURING EARLYMAMMALIAN DEVELOPMENT 57
Abstract: 57
INTRODUCTION 58
REPLICATION TIMING PROGRAM: AN ELUSIVE MEASURE OF GENOME ORGANIZATION 58
Early Experiments 58
The Lessons from X Chromosome Inactivation 60
Replication Timing Landscape on Autosomes 61
AN EVOLUTIONARILY CONSERVED EPIGENETIC FINGERPRINT 64
REPLICATION TIMING AS A QUANTITATIVE INDEX OF 3-DIMENSIONAL GENOME ORGANIZATION 65
REPLICATION TIMING REVEALS AN EPIGENETIC TRANSITION: AUTOSOMAL LYONIZATION AT THE EPIBLAST STAGE 67
REPLICATION TIMING AND CELLULAR REPROGRAMMING:FURTHER SUPPORT FOR AUTOSOMAL LYONIZATION 68
MAINTENANCE AND ALTERATION OF REPLICATION TIMING PROGRAM AND ITS POTENTIAL ROLES 69
CONCLUSION 70
ACKNOWLEDGEMENTS 70
REFERENCES 71
CHAPTER 5 PRESERVATION OF GENOMIC INTEGRITY IN MOUSE EMBRYONIC STEM CELLS 75
Abstract 75
INTRODUCTION AND HISTORICAL PERSPECTIVE 76
MUTATION FREQUENCIES IN SOMATIC CELLS 78
The Frequency of Mutation Is Suppressed in Mouse ES Cells 79
ES Cell Populations Retain Pristine Genomes by Eliminating Cells with Damaged DNA 82
Mouse ES Cells Preferentially Utilize High-Fidelity Homology-Mediated Repair Rather Than Nonhomologous End-Joining to Repair Double Strand DNA Breaks 86
CONCLUSION 88
ACKNOWLEDGEMENTS 89
REFERENCES 89
CHAPTER 6 TRANSCRIPTIONAL REGULATION IN EMBRYONIC STEM CELLS 92
Abstract: 92
INTRODUCTION 92
EMBRYONIC STEM CELLS AS A MODEL TO STUDY TRANSCRIPTIONAL REGULATION 93
TRANSCRIPTION FACTORS GOVERNING ESC PLURIPOTENCY 94
TRANSCRIPTIONAL REGULATORY NETWORK 97
TECHNOLOGIES FOR DISSECTING THE TRANSCRIPTIONAL REGULATORY NETWORK 97
THE CORE TRANSCRIPTIONAL REGULATORY NETWORK: Oct4, Sox2 AND Nanog 98
EXPANDED TRANSCRIPTIONAL REGULATORY NETWORK 100
ENHANCEOSOMES: TRANSCRIPTION FACTOR COMPLEX 102
INTEGRATION OF SIGNALING PATHWAYS TO TRANSCRIPTIONAL NETWORK 103
INTERFACE BETWEEN TRANSCRIPTIONAL AND EPIGENETIC REGULATION 104
CONCLUSION 105
ACKNOWLEDGEMENTS 105
REFERENCES 105
CHAPTER 7 ALTERNATIVE SPLICING IN STEM CELL SELF-RENEWAL AND DIFFERENTIATION 108
Abstract: 108
INTRODUCTION 108
INTRODUCTION TO ALTERNATIVE SPLICING 109
ALTERNATIVE SPLICING OF GENES IMPLICATED IN STEMNESS AND DIFFERENTIATION 109
GENOME-WIDE METHODS TO IDENTIFY AND DETECT ALTERNATIVE SPLICING EVENTS 114
REGULATION OF ALTERNATIVE SPLICING BY RNA BINDING PROTEINS 114
CONCLUSION AND PERSPECTIVES 117
ACKNOWLEDGEMENTS 118
REFERENCES 118
CHAPTER 8 MicroRNA REGULATION OF EMBRYONIC STEM CELL SELF-RENEWAL AND DIFFERENTIATION 121
Abstract: 121
INTRODUCTION: THE SELF-RENEWAL PROGRAM 121
EMBRYONIC STEM CELLS 122
miRNA BIOGENESIS AND FUNCTION 122
ESCC miRNAs PROMOTE SELF-RENEWAL 124
miRNAs INDUCED DURING ESC DIFFERENTIATION SUPPRESS THE SELF-RENEWAL PROGRAM 126
REGULATORY NETWORKS CONTROLLING miRNA EXPRESSION 128
miRNAs CAN PROMOTE OR INHIBIT DEDIFFERENTIATION TO IPS CELLS 129
miRNAs IN SOMATIC STEM CELLS 129
miRNAS IN CANCER CELLS 130
CONCLUSION 130
REFERENCES 131
CHAPTER 9 TELOMERES AND TELOMERASE IN ADULT STEM CELLS AND PLURIPOTENT EMBRYONIC STEM CELLS 134
Abstract: 134
INTRODUCTION 135
ROLE OF TELOMERES AND TELOMERASE IN ADULT SC COMPARTMENTS 137
TELOMERES AND TELOMERASE REGULATION DURING REPROGRAMMING BY SCNT 140
TELOMERES AND TELOMERASE REGULATION DURING iPS CELL GENERATION 141
TELOMERASE ACTIVATION IS ESSENTIAL FOR THE “GOOD” QUALITY OF THE RESULTING iPS CELLS 142
REGULATION OF TELOMERE REPROGRAMMING 142
CONCLUSION 143
ACKNOWLEDGEMENTS 143
REFERENCES 144
CHAPTER 10 X CHROMOSOME INACTIVATION AND EMBRYONIC STEM CELLS 148
Abstract: 148
INTRODUCTION 148
CIS ACTING FACTORS IN XCI 150
TRANS ACTING FACTORS IN XCI 152
COUNTING AND CHOICE 152
SILENCING AND MAINTENANCE OF SILENCING 157
XCI AND HUMAN ES CELLS 160
CONCLUSION 162
ACKNOWLEDGEMENTS 163
REFERENCES 163
CHAPTER 11 ADULT STEM CELLS AND THEIR NICHES 171
Abstract: 171
THE NICHE CONCEPT, DEFINITION AND HISTORICAL BACKGROUND 171
STEM CELL NICHE COMPONENTS 173
MOLECULAR PATHWAYS ASSOCIATED WITH NICHE FUNCTION 175
EXTRACELLULAR MATRIX AND CELL-CELL INTERACTIONS 176
STEM CELL NICHE DYNAMISM 177
STEM CELL NICHE AGING 178
MALIGNANT STEM CELL NICHES 179
CONCLUSION 180
REFERENCES 180
CHAPTER 12 ADULT STEM CELL DIFFERENTIATION AND TRAFFICKING AND THEIRIMPLICATIONS IN DISEASE 185
Abstract 185
DIFFERENTIATION 186
Hematopoietic Stem Cells 186
Mesenchymal Stem Cells 189
TRAFFICKING 190
Mesenchymal Stem Cells 190
Endothelial Progenitor Cells 193
Hematopoietic Stem Cells 193
CONCLUSION 195
REFERENCES 196
CHAPTER 13 VERTEBRATES THAT REGENERATE AS MODELS FOR GUIDING STEM CELLS 200
Abstract: 200
VERTEBRATE MODELS OF REGENERATION: THEIR ATTRIBUTES 200
Defining Reprogamming Processes in Regenrating Tissues 201
REGENERATION MECHANISMS OF MATURE TISSUES 202
Eye—A Model of Transdifferentiation 202
The Nervous System—A Model for Sequestered Progenitor Cells 205
Heart—A Model of Regeneration by Differentiated Cells 208
Appendages—Making Progenitor Cells from Mature Tissues 209
Guiding of Progenitor Cells through Regeneration 212
Other Signaling Factors 214
Intracellular Translation of Growth Promoting Signals 217
Molecular Factors Involved in Progenitor Cell and Blastema Formation 219
CONCLUSION 222
REFERENCES 222
CHAPTER 14 REPROGRAMMING OF SOMATIC CELLS TO PLURIPOTENCY 231
Abstract: 231
INTRODUCTION 231
SOMATIC NUCLEAR REPROGRAMMING IN FROG 232
BIRTH OF A CLONED ANIMAL, DOLLY 232
CHANGING CELL FATE BY DEFINED FACTORS, MyoD 232
REPROGRAMMING OF SOMATIC CELLS BY CELL FUSION 233
GENERATION OF INDUCED PLURIPOTENT STEM CELLS BY Sox2,Oct3/4, Klf4 AND c-Myc 233
METHODS FOR iPS CELL INDUCTION 235
MOLECULAR MECHANISM FOR iPS CELL GENERATION 236
DIRECTED CELL REPROGRAMMING: ß-CELLS FROM PANCREATIC CELLS 236
DIRECTED CELL REPROGRAMMING: NEURONAL CELLS FROM FIBROBLASTS 236
DISEASE iPS CELLS FOR CLINICAL APPLICATIONS 237
CONCLUSION 238
REFERENCES 238
INDEX 241