Preface ..................................................................... v Contributors ............................................................... xi 1. Mathematical Modeling of Stem Cells: A Complexity Primer for the Stem-Cell Biologist ......................... 1 Mark d'Inverno, Neil Theise, and Jane Prophet Introduction ............................................................ 7 Emergence ............................................................... 5 Complex Adaptive Systems with Multiple Interacting Agents ............... 7 Modeling Stem Cells and Cell Lineages as Complex Adaptive Systems ....... 8 Ramifications for Current Thinking ..................................... 13 Conclusion ............................................................. 13 References ............................................................. 14 2. Theoretical Concepts of Tissue Stem-Cell Organization .................. 17 Ingo Roeder, Joerg Galle, and Markus Loeffler Introduction ........................................................... 17 Defining Tissue Stem Cells ............................................. 18 Conceptual Challenges in Tissue Stem-Cell Biology ...................... 18 Predictive Theories and Quantitative Models ............................ 19 A New Perspective on Stem-Cell Systems ................................. 20 Modeling of the Dynamics of Clonal Competition in Hematopoietic Stem Cells .......................................... 22 Spatio-Temporal Stem-Cell Organization ................................. 26 Conceptual Novelty and Achievements .................................... 29 References ............................................................. 32 3. Mechanisms of Genetic Fidelity in Mammalian Adult Stem Cells ........... 37 James L. Sherley Evolution of Mechanisms of Mammalian Tissue Cell Genetic Fidelity: The Needs of a Few ......................................... 37 An Exact Definition for the Long-Lived Nature of ASCs .................. 39 Mutagenesis Mechanisms in ASCs ......................................... 40 Immortal DNA Strand Co-Segregation and a Carpenter's Rule for Genetic Fidelity in ASCs ............................................. 41 Implications of the Carpenter's Rule for ASC Aging, Cell Kinetics, and DNA Repair Functions ............................................. 43 Estimation of the Mutation-Avoidance Effect of an Immortal DNA Strand Mechanism in ASCs ............................................. 45 Evidence for Immortal DNA Strand Co-Segregation in ASCs ................ 47 References ............................................................. 52 4. Neural Stem Cells: Isolation and Self-Renewal .......................... 55 Hideyuki Okano, Jun Kohyama, Hiroyuki Ohba, Masanori Sakaguchi, Akinori Tokunaga, Takuya Shimazaki, and Hirotaka James Okano Introduction ........................................................... 55 In Vivo Localization of NSCs ........................................... 55 Control of the Self-Renewal and Differentiation of NSCs ................ 60 Conclusion and Perspectives ............................................ 66 References ............................................................. 66 5. Stem Cells in Mammary Epithelium ....................................... 71 Gilbert H. Smith and Robert B. Clarke Introduction ........................................................... 71 Aging and Reproductive Senescence ...................................... 72 In Vitro Studies ....................................................... 72 Mammary Stem-Cell Markers .............................................. 76 Mammary Stem Cells in Carcinogenesis ................................... 82 Pregnancy and Breast Cancer Risk ....................................... 84 Future Prospects ....................................................... 84 References ............................................................. 85 6. Lineage Tracking, Regulation, and Behaviors of Intestinal Stem Cells ... 89 Melissa H. Wong and Adrian Z. Rizvi Introduction ........................................................... 89 Intestinal Epithelium .................................................. 89 Lineage Tracking as an Approach to Understanding the Stem-Cell Behavior ............................................... 96 Tracking Stem-Cell Fate Through Understanding What Regulates Their Proliferation and Differentiation ............................. 101 Identifying Markers for Intestinal Stem Cells ......................... 109 Conclusion ............................................................ 111 References ............................................................ 111 7. Stem Cell Populations in Skin ......................................... 117 Richard P. Redvers and Pritinder Kaur Introduction .......................................................... 117 Conclusion ............................................................ 135 References ............................................................ 135 8. A Perspective on In Vitro Clonogenic Keratinocytes: A Window into the Regulation of the Progenitor Cell Compartment of the Cutaneous Epithelium .................................................. 149 Rebecca J. Morris Introduction .......................................................... 149 Cutaneous Epithelium as a Continually Renewing Tissue Containing In Vitro Clonogenic Keratinocytes ................................... 149 Functional Evidence of Stem Cells in Epidermis and Hair Follicles ..... 150 In Mice, Keratinocyte Colony Number is Genetically Defined and Quantitatively Complex .............................................. 157 Keratinocyte Colony Size is Also Genetically Defined .................. 158 Summary ............................................................... 159 References ............................................................ 159 9. Hepatic Stem Cells and the Liver's Maturational Lineages: Implications for Liver Biology, Gene Expression, and Cell Therapies ... 161 Eva Schmelzer, Randall E. McClelland, Aloa Melhem, Lili Zhang, Hsin-lei Yao, Eliane Wauthier, William S. Turner, Mark E. Furth, David Gerber, Sanjeev Gupta, and Lola M. Reid The Liver as a Maturational Lineage System ............................ 161 General Comments on Stem Cells ........................................ 168 Hepatic Stem Cells .................................................... 169 Gene Expression ....................................................... 183 Reconstitution of Liver by Cell Transplantation ....................... 188 Liver Cell Therapies-Clinical Programs ................................ 193 Conclusion ............................................................ 198 References ............................................................ 199 10. Multistage Carcinogenesis: From Intestinal Stem Cell to Colon Cancer in the Population .............................................. 215 E.Georg Luebech Introduction .......................................................... 215 A Biologically Based Multistage Model for Colon Cancer ................ 217 Adenomatous Polyps-Observations and Model Predictions ................. 221 Summary ............................................................... 225 References ............................................................ 226 11. Intestinal Stem Cells and the Development of Colorectal Neoplasia ..... 229 Stuart A.C. McDonald, Trevor Graham, Christopher S. Potten, Nicholas A. Wright, Ian P.M. Tomlinson, and Andrew G. Renehan Introduction .......................................................... 229 Basic Structure and Function of the Intestinal Crypt .................. 230 Stem-Cell Hierarchy ................................................... 234 Crypt Clonality ....................................................... 236 Intestinal Stem-Cell Repertoire ....................................... 238 The Concept of Stemness and "Immortal" DNA Strands .................... 239 Molecular Regulation of Normal Intestinal Crypt Homeostasis ........... 242 Early Molecular Events in Colorectal Tumorigenesis .................... 250 Intestinal Stem Cells and the Origin of Colorectal Cancer ............. 252 Colorectal Tumor Morphogenesis ........................................ 253 Clinical Implications and Future Directions ........................... 256 Summary ............................................................... 258 References ............................................................ 259 12. Stem Cells in Neurodegeneration and Injury ............................ 271 Reaz Vawda, Nigel L. Kennea and Huseyin Mehmet Introduction .......................................................... 271 Stem Cells ............................................................ 272 The Use of Stem Cells in Brain Disease and Injury ..................... 285 Future Perspectives ................................................... 293 References ............................................................ 293 13. Adult Stem Cells and Gene Therapy ..................................... 305 Ilaria Bellantuono and Leslie J. Fairbairn Introduction .......................................................... 305 Adult Stem Cells for Gene Therapy ..................................... 306 Gene Delivery ......................................................... 310 Hurdles to Stem-Cell Gene Therapy ..................................... 315 Conclusion ............................................................ 321 References ............................................................ 322 14. Clinical Applications of Hematopoietic Stem Cells ..................... 339 Joanne Ewing and Yvonne Summers Introduction .......................................................... 339 Clinical Use of HSCs in Transplantation ............................... 339 Autologous Stem-Cell Transplantation .................................. 341 ASCT: Malignant Diseases .............................................. 343 ASCT: Nonmalignant Diseases ........................................... 351 Allogeneic Stem-Cell Transplantation .................................. 353 Specific Clinical Indications for Allogeneic Transplant ............... 357 Cord Blood Transplantation ............................................ 363 Conclusion ............................................................ 372 References ............................................................ 373 Index ..................................................................... 389