Stem Cells And Regenerative Medicine

Front Cover......Page 1
Halftitle......Page 2
Inside Cover......Page 4
Copyright page......Page 5
Preface......Page 6
Contents......Page 8
List of Contributors......Page 12
EMBRYONIC STEM CELLS, NUCLEAR REPROGRAMMING, AND STEM CELL FATE......Page 21
1. Introduction......Page 23
2. Hematopoietic Differentiation from mESCs......Page 25
3. Hematopoietic Differentiation from hESCs......Page 26
4.1. Erythrocytes......Page 29
4.2. Megakaryocytes......Page 30
4.3. Lymphocytes and other immune cells......Page 31
4.4. Engraftment of hESC-derived hematopoietic cells......Page 32
5. Hematopoiesis and Strategies to Overcome the Immune Barriers......Page 36
6. Future Directions for Studies of Hematopoiesis from Human ES Cells......Page 38
Summary......Page 39
References......Page 40
1. Introduction......Page 47
2. Strategies for Differentiating ES Cells into Insulin-producing Cells as a Model of Pancreatic Development......Page 51
2.1. Differentiation of mouse ES cells into pancreatic cells......Page 52
2.2. Differentiation of non-human primate ES cells into insulin-producing cells......Page 57
2.3. Differentiation of human ES cells into insulin-producing cells......Page 58
References......Page 60
1. Introduction......Page 65
2.1. Cell fusion......Page 66
2.2.1. Differential chromatin structure......Page 70
2.2.2. Differential gene expression......Page 71
2.3. Nuclear cloning......Page 72
2.3.1. Release of transcription factors from nuclei by the chromatin remodeling protein ISWI......Page 74
2.3.3. Nucleolar disassembly by FRGY2a/b......Page 75
2.3.4. Replacement of linker histone by nucleoplasmin......Page 77
Conclusion......Page 78
References......Page 79
1. Introduction......Page 83
2.1. Self-renewal and differentiation......Page 84
2.2. Stem cell types......Page 86
3.1. The cell cycle......Page 87
3.2. Cell cycle machinery......Page 88
3.3. G1 progression......Page 89
4.1. Deciding to divide......Page 92
4.2. Proliferative outcomes......Page 97
4.3. Molecular control of cell cycle progression......Page 99
5. Re-Evaluating the Role of Cyclin–CDKs in Stem Cell Proliferation......Page 103
6. Implications for Regenerative Medicine......Page 107
References......Page 108
ADULT STEM CELLS......Page 113
1.1. Culture conditions......Page 115
1.3. Characteristics of MAPCs......Page 117
1.4.1. Mesenchymal lineage differentiation......Page 118
1.4.2. Neuroectodermal differentiation......Page 119
1.4.4. Endothelial differentiation......Page 120
1.4.6. Pancreatic β-cell differentiation......Page 121
1.6.1. Hematopoietic cell differentiation......Page 122
1.6.2. Endothelium differentiation......Page 123
1.8. Muscle transplantation......Page 124
1.9. Mechanisms underlying pluripotency of MAPCs......Page 125
References......Page 127
2. Adult Stem Cells and Niches......Page 131
3. Ocular Surface Epithelial Stem Cells......Page 132
4. Candidate Markers of Corneal Epithelial Stem Cells......Page 134
5. Enrichment of Corneal Epithelial Stem Cells......Page 138
6. Corneal Epithelial Stem Cell Niche......Page 139
7. Conjunctival Epithelial Stem Cells......Page 142
8. Limbal Stem Cell Deficiency......Page 144
9. Surgical Therapy for Corneal Epithelial Stem Cell Deficiency......Page 145
9.1. Conjunctival transplantation......Page 146
9.2. Limbal transplantation......Page 147
9.2.2. Cadaveric Conjunctival Limbal Allograft (c-CLAL)......Page 148
9.2.4. Keratolimbal Allograft (KLAL)......Page 150
9.3. Ex vivo limbal stem cell expansion......Page 151
9.4. Amniotic membrane transplantation......Page 152
Summary......Page 153
References......Page 154
STEM CELLS FOR MUSCLE AND HEART......Page 163
1. Introduction......Page 165
2.1. The terminology of muscle cells......Page 167
2.2. Embryonic muscle cells originate from mesodermal precursors (Fig. 1)......Page 168
3.2. Molecular mechanisms in satellite cell activation and differentiation......Page 170
3.4. Developmental origin of satellite cells......Page 173
3.5. Multipotential differentiation capability of satellite cells......Page 174
3.6. Micro-RNAs regulate muscle differentiation......Page 176
3.7. Muscle side population (SP) cells (Fig. 5)......Page 177
3.8. Other myogenic progenitor cells in muscle......Page 181
3.9. Hematopoietic potential cells in muscle......Page 183
4. Cardiac Stem/Progenitor Cells......Page 185
5. Future Directions......Page 186
References......Page 187
1. Introduction: Extraocular Muscle Properties Distinct from Limb Skeletal Muscle......Page 197
2. Myogenic Precursor Cells in Skeletal Muscle......Page 198
3. Myogenic Precursor Cells in Extraocular Muscle......Page 200
4. Constitutive Differences in the Myogenic Precursor Cells in EOM and Limb Skeletal Muscle......Page 203
5. Enriched Populations of Myogenic Precursor Cells in the EOMs......Page 204
References......Page 206
1. Introduction......Page 211
2. Cell Therapy Can Reverse Left Ventricular Remodeling in Heart Failure......Page 213
3. Cell Therapy Can Prevent Left Ventricular Remodeling and Halt Atherosclerosis......Page 222
4. Uncommitted Cardiac Precursors — Simply a Better Cell or a New Way Forward?......Page 227
5. Cell-derived Autologus Organs — Is that What the Future Holds?......Page 229
6.1. Step 1: Creating a registry and biorepository will let us examine existing data and guide the next generation of clinical trials......Page 230
6.2. Step 2: Comparison of different cell types will define the “best cell”......Page 231
6.3. Step 3: The next generation of clinical trials needs to be based on the consensus regarding protocol design and outcome measurements......Page 233
Summary......Page 234
References......Page 235
1. Introduction......Page 241
2.1.1. Can the cardiomyocytes replicate?......Page 242
2.1.2. Types of cardiac progenitor cells......Page 244
2.1.3. Origin of the cardiac progenitor cell......Page 245
2.1.4. Myocardial regeneration from cardiac progenitor cells......Page 246
2.2. Bone marrow-derived stem cells......Page 250
2.3.1. Phenotype and differentiation potential......Page 251
2.3.2. Mesenchymal stem cells for myocardial repair......Page 252
2.4. Multipotent adult progenitor cells......Page 253
2.6. Endothelial progenitor cells......Page 255
2.7. Umbilical cord blood stem cells......Page 256
3. Cell Transplantation in Nonischemic Cardiomyopathy......Page 257
4. Clinical Trials of Stem Cell Treatment in Heart Disease......Page 258
5. Techniques for Enhancing the Efficacy of Stem Cell Therapy......Page 265
5.2. Mobilization......Page 266
5.4. Function and survival......Page 267
5.5. Use of biomaterials to design the microenvironment......Page 269
References......Page 271
STEM CELLS FOR THE NERVOUS SYSTEM......Page 283
1. Introduction......Page 285
1.1.2. Neural progenitor cells (NPCs)......Page 286
1.1.4. Embryonic stem cells......Page 287
1.1.6. Hi-arr- β-gal Tg mice......Page 289
1.1.8. ROSA26 mice......Page 291
2.1. Characterization and differentiation of the β-gal-expressing
NPCs in vitro......Page 292
2.1.2. NPCs from hi-arr- β-gal mice after 3 and 6 weeks......Page 293
2.1.3. NPCs from GFAP- β-gal mice after 2 and 6 weeks......Page 295
2.1.4. NPCs from ROSA26 mice at 1, 2 and 6 weeks......Page 296
2.2. Summary......Page 297
3.1. NPC transplantation into the brain......Page 298
3.3. Anterior chamber inoculation of NPCs and analysis for Xgal+ cells......Page 299
3.4. IP inoculation of NPCs......Page 301
3.5. Engraftment of donor cells in other sites......Page 302
3.6. Summary......Page 303
3.7. Prospective studies/interpretation......Page 304
References......Page 305
2.1. The development of NSCs......Page 311
2.2. Defining features of neural stem and progenitor cells......Page 313
2.3. NSCs in culture......Page 314
2.4. Where are NSCs found in the brain?......Page 317
3.1. In vivo SVZ neurogenesis......Page 318
3.2. Functional implications of SVZ neurogenesis......Page 319
3.3. Hippocampal NSCs......Page 320
3.4. Functional implications of hippocampal neurogenesis......Page 322
4.1. Introduction to neuroregeneration......Page 323
4.2. Methodological considerations for the study of neuroregeneration......Page 324
4.3. NSC plasticity......Page 325
4.4.1. Regulating NSC behavior in vivo......Page 326
4.4.2. Functional benefits of injury-induced neurogenesis?......Page 329
4.4.3. Evidence for human NSC mobilization......Page 332
4.5. Oligodendrocyte precursors: Stem cells hiding in the parenchyma?......Page 333
4.6. Neuroregeneration using exogenous cells......Page 335
Conclusion......Page 337
References......Page 338
1. Introduction......Page 347
2. The Discovery of Cochlear Stem Cells/Progenitors in the Mammalian Organ of Corti......Page 349
3. The Markers of Cochlear Stem Cells/Progenitors......Page 350
4. The Quiescent State of Cochlear Stem Cells/Progenitors in the Adult Mammalian Organ of Corti......Page 354
5. The Maintenance of Cochlear Stem Cells/Progenitors......Page 357
6. The Oligopotency of Cochlear Stem Cells/Progenitors......Page 359
7. The Specific Factors for “Priming” Cochlear Stem Cells/Progenitors......Page 361
8. The Differentiation of Cochlear Stem Cells/Progenitors......Page 362
9. The Applications of Cochlear Stem Cells/Progenitors in Degenerative Hearing Disorders......Page 366
10.2. Promotion of endogenous cochlear stem cell/progenitor proliferation and differentiation......Page 367
10.3. Use of nanoparticles to deliver factors......Page 368
References......Page 369
1. Introduction......Page 375
1.1. Nonvascular routes of delivery of stem cells......Page 376
1.2.2. Intra-arterial route of delivery......Page 378
1.2.3. Optimization of intravascular delivery systems for stem cells......Page 381
2. Traumatic Brain Injury......Page 383
2.1.1. Experimental studies of intravascular stem cell therapies in TBI......Page 384
2.1.2. Choice of stem cell type in TBI......Page 385
2.1.4. Optimal timing of stem cell therapy in TBI......Page 386
2.1.5. Optimal intravascular route of delivery in TBI......Page 387
3.1.1. Choice of stem cell type in SCI......Page 388
3.1.3. Optimal timing of stem cell therapy in SCI......Page 389
3.1.4. Optimal intravascular route of delivery in SCI......Page 390
4. Ischemic Stroke......Page 391
4.1.1. Choice of stem cell type in ischemic stroke......Page 392
4.1.3. Optimal timing of stem cell therapy in ischemic stroke......Page 393
5. Intracerebral Hemorrhage......Page 395
5.1.1. Choice of stem cell type in ICH......Page 396
5.1.4. Optimal intravascular route of delivery in ICH......Page 397
6.1. Molecular therapies for brain tumors......Page 398
6.2. Cellular-Vector-mediated molecular therapy (“Bystander killing”) for malignant brain neoplasms......Page 401
7. Multiple Sclerosis......Page 402
8. Epilepsy......Page 403
10. Muscular Dystrophy......Page 404
11.1. Peripheral neuropathy......Page 405
12. Sensorineural Deafness......Page 406
References......Page 407
1. Introduction......Page 417
2. Endogenous Stem Cells in the Adult Inner Ear......Page 418
3. Stem Cell Transplants into the Inner Ear......Page 421
3.1. Neural stem cells migrate within the inner ear and are influenced by the cellular environment......Page 422
3.2. Multipotent adult progenitor cells are candidates for replenishing different cell types......Page 424
3.2.2. MAPC stem cell transplants......Page 425
3.4. Embryonic stem cells can be induced to inner ear progenitor cells......Page 429
3.5. Bone marrow hematopoietic stem cells differentiate toward inner ear fibrocytes......Page 430
Future Challenges......Page 431
References......Page 432
STEM CELLS FOR LIVER AND KIDNEY......Page 437
2. Stem Cells and Kidney Development......Page 439
4. Acute Renal Failure......Page 441
4.1. Renal regeneration following acute renal failure......Page 442
5. Adult Renal Stem Cells......Page 443
5.1. Label-retaining cells......Page 446
5.3. Candidate markers used to isolate renal stem cells......Page 447
5.4. Selective culture conditions......Page 448
6. Cellular Therapy of Renal Disease......Page 449
6.1. Therapy of acute renal failure......Page 450
6.1.1. Functional improvement......Page 452
6.2. Therapy of glomerular disease......Page 453
7. Future Directions......Page 454
References......Page 455
1. Introduction......Page 465
2.1.1. Fetal liver progenitor cells......Page 466
2.1.2. Cell surface markers of fetal liver progenitor cells......Page 467
2.2.1. Oval cells......Page 468
2.2.2. Small hepatocyte-like progenitor cells (SHLPs)......Page 470
2.3. Liver cancer stem cells......Page 471
3.1.2. WB-F344 epithelial cells......Page 472
3.1.5. Human liver cell lines......Page 473
3.2.1. Differentiation of mouse ES cells into hepatic cells......Page 474
3.2.3. In vitro and in vivo function of ES cell-derived hepatic cells......Page 477
3.3.2. Multipotent adult progenitor cells differentiating into liver cells......Page 478
3.4. Liver stem cells and transdifferentiation......Page 479
3.4.2. Noncharacterized liver stem cells in the pancreas......Page 480
3.4.4. Salivary gland cells to become hepatocytes......Page 481
4.1. Liver tissue turnover under normal conditions......Page 482
4.2. Liver regeneration after acute liver injury......Page 483
4.3. Progenitor-dependent liver regeneration under chronic injury......Page 485
5. Liver Repopulation......Page 486
5.1. Animal models for hepatocyte transplantation assay......Page 487
5.1.3. Retrorsine-treated animals......Page 488
5.2. Liver repopulations from mature hepatocytes......Page 490
5.3. Liver repopulations from fetal liver progenitor cells......Page 491
5.4.1. Liver repopulations from oval cells......Page 492
5.4.3. Liver repopulations from ES cell-derived hepatic cells......Page 493
Conclusion......Page 495
References......Page 496
TECHNOLOGY FOR PRODUCTION OF STEM CELLS......Page 505
2. Preclinical Studies......Page 507
4.1. Facility......Page 509
5. Technical Expertise......Page 511
6. Regulatory Support......Page 512
8.1. Technology transfer......Page 513
8.2. Cell isolation......Page 515
8.3. Culture/expansion......Page 516
8.4. Cell banks......Page 517
8.5. Master cell banks......Page 518
9. Other Issues Related to Production......Page 519
9.2. Lot release/quality control testing......Page 520
10. Product Administration......Page 522
11.1. cGMP/cGTP......Page 524
11.2. Investigational new drug (IND) application: Chemistry, manufacturing, and controls (CMC)......Page 525
References......Page 529
1. Introduction......Page 533
2.1. Important variables defining the “state” of stem cells......Page 535
2.2. Cell characterization......Page 536
2.3. Phenotype characterization......Page 537
2.4. Averaged properties and distributed properties hyperproducing cell line......Page 540
2.5. Multiparametric characterization of stem cells......Page 542
2.6. Functional characterization......Page 545
3. Kinetic Description of Population Dynamics......Page 547
3.1. Specific rates......Page 548
4.1. Environment......Page 551
4.2. Characterization of the environment......Page 552
5.1. Traditional Monod model......Page 554
5.2. Modeling stem cell culture......Page 556
Conclusion......Page 558
References......Page 559
Index......Page 563