Biology and Therapeutic Application of Mesenchymal Cells (eBook)

The biology and therapeutic application of mesenchymal cells 1
Contents 11
Contributors 29
Editor's preface 37
Section I: An overview of mesenchymal stem cells and mesenchymal stromal cells 39
Chapter 1: The mesenchymal stem cell, the mesenchymal stromal cell, and the mesenchymal stromal cell exosome 41
1.1 Nomenclature 41
1.2 The mesenchymal stem cell 41
1.3 The mesenchymal stromal cell 42
1.4 The mesenchymal stromal cell exosome and extracellular vesicles 44
References 45
Chapter 2: The nomenclature of mesenchymal stem cells and mesenchymal stromal cells 46
2.1 Introduction 46
2.2 Historical perspective 46
2.3 The need for common terminology and definition: the International Society for Cellular Therapy white papers of the mid-2000s 47
2.4 Updating terminology 47
References 48
Section II: The isolation and ex vivo expansion of mesenchymal stromal cells 49
Chapter 3: The isolation and expansion of mesenchymal stromal cells from bone marrow 51
3.1 Introduction 51
3.2 Stem cells 52
3.3 Isolation and characterization of bone marrow mesenchymal stromal cells 52
3.3.1 Cell surface markers 53
3.3.2 Chemokine receptor display 53
3.3.3 Mesodermal differentiation capability 55
3.4 The immunomodulatory properties of mesenchymal stromal cells 55
3.5 The transcriptome of mesenchymal stromal cells 56
References 58
Chapter 4: The biology and clinical applications of mesenchymal stromal cells derived from human gestational tissues 62
4.1 Introduction 62
4.2 Isolation of placental mesenchymal stromal cells 63
4.3 Characteristics of fetally derived mesenchymal stromal cells isolated from gestational tissues 64
4.3.1 Amniotic-membrane-derived mesenchymal stromal cells 64
4.3.2 Chorionic-membrane-derived mesenchymal stromal cells 64
4.4 Characteristics of maternally derived mesenchymal stromal cells isolated from gestational tissue (the decidua) 65
4.5 Comparison of mesenchymal stromal cells from fetal and maternal tissues isolated from gestational tissues 65
4.6 Comparison of gene expression profiles between human term-placenta-derived mesenchymal stromal cells, human adult bone-marrow-derived mesenchymal stromal cells, and human umbilical-cord-derived unrestricted somatic stem cells 66
4.7 Preclinical mesenchymal stromal cell studies 66
4.8 Clinical applications of placental mesenchymal stromal cells 67
4.9 Manufacturing clinical-grade placenta-derived mesenchymal stromal cells 67
4.9.1 Phase 1 clinical trials using unrelated major-histocompatibility-unmatched placenta-derived mesenchymal stromal cells 68
4.10 Conclusions 68
References 68
Chapter 5: Human placenta-derived mesenchymal stem/stromal cells: fetal and maternal origins and critical parameters for ex vivo expansion 70
5.1 Introduction 70
5.2 Mesenchymal stem/stromal cells: a consensus definition? 70
5.3 Prenatal and perinatal tissue sources of mesenchymal stem/stromal cells 71
5.4 Fetal tissue-derived mesenchymal stem/stromal cells 71
5.5 Placental and adnexal stem and progenitor cells 71
5.6 Comparison of mesenchymal stem/stromal cells from different gestational sources 71
5.7 Consensus classification of human placental mesenchymal stem/stromal cells? 72
5.8 Differentially isolating fetal or maternal mesenchymal stem/stromal cells from term placental villi 72
5.9 Confounding factors for the isolation of fetal placental mesenchymal stem/stromal cells from chorionic villi 72
5.10 Assumptions from the literature: lack of data, specific assays, and specific methodological detail 73
5.11 Methods for determining fetal and maternal mesenchymal stem/stromal cells in a cultured cell population 73
5.12 A novel method to isolate fetal and maternal placental mesenchymal stem/stromal cells 74
5.13 Understanding the maternal origin of the placental mesenchymal stem/stromal cells: the septa 74
5.14 Conclusions and future directions 74
Acknowledgments 75
References 75
Section III: The cellular and molecular biology of mesenchymal stromal cells 77
Chapter 6: Epigenetic regulation of mesenchymal stem/stromal cell growth and multipotentiality 79
6.1 Introduction 79
6.2 Mesenchymal stromal/stem cells 80
6.3 Epigenetics 80
6.4 DNA methylation and histone modifications in mesenchymal stem/stromal cells 83
6.5 Epigenetic regulation of osteogenic differentiation 83
6.6 Epigenetic regulation of adipogenic differentiation 85
6.7 Epigenetic regulation of myogenic differentiation 86
6.8 Epigenetic regulation of chondrogenic differentiation 86
6.9 Epigenetic regulation of mesenchymal stem/stromal cell lifespan and senescence 90
6.10 Regulation of epigenetic modifications in mesenchymal stem/stromal cells for clinical use 90
6.11 Conclusions 90
References 91
Chapter 7: Biological changes in human mesenchymal stromal cells during monolayer culture 96
7.1 Introduction 96
7.2 Mesenchymal stromal cell isolation from bone marrow 97
7.3 Mesenchymal stromal cell isolation from adipose tissue 98
7.4 Biological characteristics 98
7.4.1 Morphology and colony formation 98
7.4.2 Growth kinetics 99
7.4.3 In vitro multipotency 100
7.4.4 Gene expression 100
7.4.5 Cell surface marker profile 101
7.4.6 Secretory profile 104
7.5 Influences on tissue culture parameters 104
7.5.1 Seeding density 104
7.5.2 Culture medium and supplementation 105
7.5.3 Growth factors 105
7.5.4 Xeno-free media 105
7.5.5 Platelet-derived supplements 105
7.5.6 Serum-free media 106
7.5.7 Hypoxia 106
7.6 Implications for basic and clinical research 106
7.6.1 Trial disparity 106
7.6.2 Alternative culture systems 107
7.7 Conclusions and future directions 108
References 108
Chapter 8: The effect of three-dimensional aggregates on the biology of mesenchymal stromal cells 113
8.1 Three-dimensional multicellular aggregates 113
8.2 Three-dimensional aggregates of mesenchymal stromal cells 114
8.3 Mechanism of mesenchymal stromal cells self-assembly into three-dimensional aggregates 115
8.3.1 Cell-cell contact 115
8.3.2 Extracellular matrix and the cytoskeleton 115
8.3.3 Mesenchymal stromal cells heterospheroids 116
8.4 Mechanisms of aggregate-mediated mesenchymal stromal cell functional enhancement 116
8.4.1 Role of cell adhesion molecules in the fate decision of mesenchymal stromal cell three-dimensional aggregates 117
8.4.2 Effects of extracellular matrix, cytoskeleton, and morphology on mesenchymal stromal cell lineage commitment in three-dimensional aggregates 118
8.4.3 Role of molecular milieu and hypoxia-inducible factor activation 118
8.4.4 Metabolism changes in three-dimensional aggregates of mesenchymal stromal cells 119
8.4.5 Enhanced anti-inflammatory properties of three-dimensional aggregates of mesenchymal stromal cells 119
8.5 Bioreactor systems for three-dimensional aggregate production 119
8.5.1 Scale-up and dynamics of culture 119
8.5.2 Spinner flasks 120
8.5.3 Rotary wall vessel 120
8.5.4 Rotary orbital system 121
8.5.5 Comparison of spinner flask and rotary wall vessel 121
8.5.6 Other systems 122
8.6 Transplantation of three-dimensional mesenchymal stromal cell aggregates in preclinical animal models of disease 122
8.6.1 Enhanced secretory properties of mesenchymal stromal cells aggregates 122
8.6.2 Immunomodulation by mesenchymal stromal cell aggregates 122
8.6.3 Enhanced multilineage differentiation of three-dimensional mesenchymal stromal cells aggregates 122
8.6.4 Recapitulation of mesenchymal condensation and osteochondral differentiation in bone and cartilage regeneration 124
References 125
Chapter 9: Cell-cell signaling pathways that regulate mesenchymal stromal cell differentiation 129
9.1 Introduction 129
9.2 Mesenchymal stromal cell signaling is dependent on its type 129
9.3 Identity of bone-marrow-derived mesenchymal stromal cells 130
9.4 Mesenchymal stromal cell signaling in the stem cell niche 131
9.5 Regulation of mesenchymal stromal cell differentiation by the TGF-?/BMP signaling pathway 133
9.6 Regulation of mesenchymal stromal cell differentiation by the Wnt signaling pathway 135
9.7 Conclusions 137
References 137
Chapter 10: Regulation of mitochondrial transport in mesenchymal stromal cells 142
10.1 Introduction 142
10.2 Intercellular organelle transport 143
10.2.1 Intercellular communication 143
10.2.2 Mitochondrial biology 143
10.2.3 Intercellular mitochondrial transport/mitochondrial donation 143
10.3 Mesenchymal stromal cells as potential mitochondrial donors 145
10.3.1 Mechanism of intercellular mitochondrial transport regulation 146
10.4 Strategies to improve mitochondrial delivery to target cells 148
10.5 The road ahead 149
References 149
Chapter 11: The regulation of adipogenesis from adipose-derived stem/stromal cells 152
11.1 Introduction 152
11.2 Adipose-derived stem/stromal cells 153
11.2.1 Preparation and molecular characterization of adipose-derived stem/stromal cells 153
11.2.2 Differentiation capacity of adipose-derived stem/stromal cells 154
11.3 Process of adipogenic differentiation from adipose-derived stem/stromal cells 154
11.3.1 Adipocyte development program 154
11.3.2 Signaling pathways associated with adipogenic differentiation 155
11.4 Regulation of adipogenic differentiation from adipose-derived stem/stromal cells 156
11.4.1 Transcriptional regulation 156
11.4.2 Epigenetic regulation 157
11.4.3 Post-transcriptional regulation 159
11.5 The future 163
References 163
Chapter 12: Modulation of osteogenic differentiation in mesenchymal stromal cells 169
12.1 Introduction 169
12.2 Biology 170
12.2.1 Sources of mesenchymal stromal cells 170
12.2.2 Cellular regulation of osteogenic differentiation from mesenchymal stromal cells 170
12.2.3 Molecular regulation of osteogenic differentiation from mesenchymal stromal cells 172
12.2.4 Factors regulating homing of mesenchymal stromal cells to bone 174
12.2.5 In vivo detection and contribution of mesenchymal stromal cells to osteogenesis 175
12.2.6 Regulating the immune system for bone formation 176
12.3 Clinical applications of mesenchymal stromal cells in bone disorders 176
12.3.1 Bone regeneration 176
12.3.2 Osteoarthritis 177
12.3.3 Osteogenesis imperfecta 178
12.4 Summary 179
References 179
Chapter 13: The role of glycogen synthase kinase-3 inhibitors on bone remodeling 186
13.1 Overview of glycogen synthase kinase-3 186
13.2 The response of skeletal cells to glycogen synthase kinase-3 inhibitors in vitro 187
13.2.1 Lithium chloride 187
13.2.2 SB-216763 and SB-415286 189
13.2.3 6-bromoindirubin-3'-oxime 190
13.2.4 LY603281-31-8 191
13.2.5 CT99021/CHIR99021 191
13.2.6 AR28 (AZD2858), AR79, and AZ13282107 192
13.3 Bone anabolism through inhibition of glycogen synthase kinase-3 in vivo 193
13.3.1 Functional Wnt/?-catenin responses in Xenopus laevis model systems 194
13.3.2 Progenitor cell involvement in bone anabolism in vivo 194
13.3.3 Alteration in bone resorption in vivo 196
13.4 Impact of glycogen synthase kinase-3 inhibition in bone disease 197
13.4.1 Osteopenia and osteoporosis 197
13.4.2 Methotrexate-induced bone loss 198
13.4.3 Fracture healing 198
13.4.4 Multiple myeloma-associated bone disease 199
13.4.5 Periodontal disease 199
13.4.6 Clinical findings with lithium 199
13.5 Summary 200
References 201
Chapter 14: Early molecular events during in vitro chondrogenesis 205
14.1 Introduction 205
14.2 Adult articular cartilage 206
14.3 Developmental chondrogenesis 206
14.4 Molecular aspects of in vivo chondrogenesis 207
14.5 Determinants of in vitro chondrogenesis 209
14.6 Tissue source of mesenchymal stromal cells 209
14.6.1 In vitro cell culture 209
14.7 Three-dimensional culture systems and bioscaffolds 210
14.8 Epigenetic changes during early in vitro chondrogenesis 210
14.8.1 An introduction to epigenetics 210
14.8.2 DNA methylation of the COL2A1 and COL10A1 promoters 211
14.8.3 DNA methylation of promoters in other chondrogenesis candidate genes 211
14.8.4 Genome-wide map of quantified epigenetic changes during in vitro chondrogenesis of bone marrow mesenchymal stromal cells 212
14.8.5 Epigenetics: conclusions 213
14.9 Role of microRNAs during early in vitro chondrogenesis 214
14.9.1 An introduction to microRNAs 214
14.9.2 Role of miRNA-140 in developmental chondrogenesis 215
14.9.3 miR-140 targets identified in vivo and in vitro 216
14.9.4 Defining the role of miR-140 during chondrogenic differentiation of mesenchymal stromal cells and dedifferentiation of articular chondrocytes 216
14.9.5 Impact of microRNAs other than miR-140 on chondrogenic differentiation of mesenchymal stromal cells 217
14.9.6 MicroRNAs in chondrogenesis: conclusions 219
14.10 Early changes in gene expression during in vitro chondrogenesis 220
14.10.1 Genes involved in collagen fibrillogenesis 221
14.10.2 Genes involved in synthesis of proteoglycans and glygosaminoglycans 221
14.10.3 Transcription factor genes 221
14.10.4 Genes encoding other important cartilage molecules 222
14.10.5 Genes encoding unwanted molecules 222
14.10.6 Effect on gene expression of changes in the differentiation cocktail 222
14.11 Conclusions 224
References 224
Chapter 15: The role of the extracellular matrix in the differentiation of mesenchymal stromal cells 229
15.1 Summary 229
15.2 Multipotency of mesenchymal stromal cells 229
15.3 The extracellular matrix and mesenchymal stromal cell differentiation 230
15.3.1 The role of osteopontin in mesenchymal stromal cell differentiation 231
15.3.2 Geometric cues in mesenchymal stromal cell differentiation 231
15.3.3 Crosstalk between the extracellular matrix and mesenchymal stromal cells 231
15.4 Conclusions and future perspectives 232
Acknowledgments 232
References 232
Chapter 16: Effects of hypoxic culture on bone marrow multipotent mesenchymal stromal cells: from bench to bedside 234
16.1 Introduction 234
16.2 Multipotent mesenchymal stromal cells 234
16.3 Criteria for defining human multipotent stromal cells 235
16.4 Problems encountered in the clinical application of multipotent mesenchymal stromal cells 235
16.5 The hypoxic niche of multipotent mesenchymal stromal cells 235
16.6 Involvement of hypoxia-inducible factor-1? in hypoxia-mediated effects 236
16.7 Effects of hypoxic culture on glucose metabolism and oxidative stress of multipotent mesenchymal stromal cells 236
16.8 Effects of hypoxic culture on the apoptosis of multipotent mesenchymal stromal cells 237
16.9 Effects of hypoxic culture on expansion and life span of multipotent mesenchymal stromal cells 237
16.10 Effects of hypoxic culture on maintaining self-renewal and differentiation potential of multipotent mesenchymal stromal cells 238
16.11 Differentiation of multipotent mesenchymal stromal cells under hypoxic conditions 238
16.12 Effects of hypoxic culture on secretion of paracrine factors by multipotent mesenchymal stromal cells 239
16.13 Effects of hypoxic culture on engraftment of multipotent mesenchymal stromal cells 240
16.14 Effects of hypoxic culture on allogeneic transplantation of multipotent mesenchymal stromal cells 240
16.15 Conclusions 241
Acknowledgments 241
References 241
Chapter 17: The role of cyclic tensile strain on osteogenesis and angiogenesis in human mesenchymal stem/stromal cells 246
17.1 Introduction 246
17.2 Applications of tensile strain: an interpretation from physiological stimuli in vivo to bioreactors in vitro 247
17.2.1 Uniaxial tensile strain 247
17.2.2 Equi-/biaxial tensile strain 248
17.3 Mechanical sensing of mesenchymal stem/stromal cells 249
17.3.1 Integrins and the cytoskeleton 249
17.3.2 The nucleoskeleton and lamins 250
17.3.3 Primary cilia 250
17.3.4 Stretch-activated calcium channels 251
17.3.5 The glycocalyx 251
17.4 The molecular response of mesenchymal stem/stromal cells to cyclic tensile strain 252
17.4.1 Restructuring of mesenchymal stem/stromal cells and the surrounding extracellular matrix by mesenchymal stem/stromal cells in response to cyclic tensile strain 253
17.4.2 Mesenchymal stem/stromal cell secretomes that induce further responses from other cells 254
17.5 Summary 255
Acknowledgments 255
References 255
Chapter 18: The evolving concept of mesenchymal stromal cells in regenerative medicine: from cell differentiation to secretome 260
18.1 Mesenchymal stromal cells 260
18.2 The mesenchymal stromal cell secretome 262
18.2.1 Concept 262
18.2.2 Characterization techniques 262
18.3 The mesenchymal stromal cell secretome in transplantation and regenerative medicine 263
18.3.1 Graft-versus-host-disease 263
18.3.2 The central nervous system 264
18.4 The peripheral nervous system 267
18.5 Future perspectives 268
References 269
Chapter 19: The secretome of mesenchymal stem/stromal cells undergoing chondrogenic differentiation and those undergoing osteogenic or adipogenic differentiation 274
19.1 Introduction to protein secretion and the analysis of secretomes 274
19.2 Analysis of mesenchymal stem/stromal cell secretomes using proteomic approaches 275
19.2.1 Approaches to obtaining secretome samples 275
19.2.2 Experimental strategies for in vitro secretome analysis of mesenchymal stem/stromal cells 275
19.3 Analysis of the secretome of mesenchymal stem/stromal cells undergoing chondrogenesis 280
19.4 Characterization of chondrogenesis markers by secretome analysis 280
19.5 Characterization of osteogenesis markers by secretome analysis 285
19.6 Characterization of adipogenesis markers by secretome analysis 285
19.7 Conclusions and future perspectives 285
References 285
Chapter 20: Mesenchymal stromal cell extracellular vesicles/exosomes 288
20.1 From cell to secretion to exosome 288
20.1.1 Mesenchymal stromal cells 288
20.1.2 Cell secretion 289
20.1.3 Mesenchymal stromal cell extracellular vesicles as the active therapeutic factor 289
20.2 Extracellular vesicles 289
20.2.1 Exosome biology and general functions 290
20.3 The therapeutic use of exosomes 290
20.3.1 Mesenchymal stromal cell exosomes 291
20.3.2 Characterization of mesenchymal stromal cell exosomes 292
20.3.3 The biochemical potential of mesenchymal stromal cell exosomes 292
20.3.4 Biochemical potency 293
20.3.5 Glycolysis 294
20.3.6 Proteasome activity 294
20.3.7 Signaling: adenosine signaling 294
20.3.8 Inhibition of complement activation 294
20.3.9 Restoring homeostasis 294
20.3.10 Bioenergetic homeostasis 295
20.3.11 Immune homeostasis 295
20.4 The clinical translation of mesenchymal stromal cell exosomes 296
20.5 Conclusions 296
References 296
Chapter 21: Role of tunneling nanotube crosstalk with distressed cardiomyocytes in controlling the heart repair potential of mesenchymal stromal cells 302
21.1 Introduction 302
21.2 Mesenchymal stromal cells as a promising tool to regenerate damaged heart tissue 302
21.2.1 Degenerative cardiac diseases: a major public health problem 302
21.2.2 Mesenchymal stromal cells: a promising tool to treat the effects of myocardial infarction 303
21.2.3 Mechanisms underlying the regenerative effects of mesenchymal stromal cells 304
21.3 Tunneling nanotubes: a universal route of intercellular communication between distant cells 306
21.3.1 Structural diversity of tunneling nanotubes 307
21.3.2 Mechanisms and factors involved in tunneling nanotube formation 307
21.3.3 The diversity of compounds transferred by tunneling nanotubes and their physiological relevance 309
21.4 Tunneling nanotubes: a novel cell-to cell communication pathway improving the cardiac regenerative properties of mesenchymal stromal cells 311
21.4.1 Evidence of tunneling-nanotube-mediated communications between stromal cells and cardiomyocytes 311
21.4.2 Tunneling nanotube cell-to-cell communication with mesenchymal stromal cells rejuvenates distressed cardiomyocytes through a progenitor-like state 313
21.4.3 Tunneling nanotube cell-to-cell communication with distressed cardiomyocytes stimulates the paracrine repair function of mesenchymal stromal cells 315
21.5 Conclusions 317
References 318
Chapter 22: The preferential homing of mesenchymal stromal cells to sites of inflammation 324
22.1 Introduction 324
22.2 Molecular mechanisms of migration 325
22.2.1 Chemokines 325
22.2.2 Integrins 327
22.2.3 Toll-like receptors 327
22.2.4 Matrix metalloproteinases 328
22.2.5 Growth factors 329
22.3 The inflammatory milieu 329
22.3.1 Passive migration 329
22.3.2 Hypoxia 329
22.3.3 Cytokines 330
22.3.4 Complement 331
22.3.5 Macrophages 332
22.4 Mesenchymal stromal cell extravasation 332
22.5 In vivo migration 332
22.5.1 In vivo migration studies 332
22.5.2 Controversies surrounding in vivo migration 335
22.5.3 Real-time in vivo imaging 339
22.6 Optimizing homing 340
22.6.1 Culture conditions 340
22.6.2 Pretreatment of mesenchymal stromal cells 341
22.6.3 Cell engineering 341
22.6.4 The host environment 342
22.7 Conclusions 343
References 344
Chapter 23: The role of chemokines in mesenchymal stromal cell homing to sites of inflammation, including infarcted myocardium 352
23.1 Summary 352
23.2 Introduction 352
23.3 Homing capacity of mesenchymal stromal cells 353
23.4 Homing ability of mesenchymal stromal cells and their therapeutic effects 354
23.5 Mechanisms of leukocyte trafficking to sites of inflammation 354
23.6 Potential ligands/receptors for mesenchymal stromal cell homing 355
23.7 Chemokine involvement in mesenchymal stromal cell homing 355
23.7.1 CCR1 and CCR2 involvement in mesenchymal stromal cell homing 355
23.7.2 The CXCR4-SDF-1 axis in mesenchymal stromal cell homing 356
23.7.3 Other chemokines 357
23.8 Pretreatment of mesenchymal stromal cells with cytokines and growth factors 357
23.9 Summary and future prospects 357
Acknowledgments 357
References 358
Chapter 24: Live cell imaging and single cell tracking of mesenchymal stromal cells in vitro 361
24.1 Introduction 361
24.2 Technical considerations 364
24.2.1 Equipment, software, and hardware requirements 364
24.2.2 Image acquisition parameters 365
24.2.3 Image processing 365
24.2.4 Data storage 366
24.3 Single cell tracking and analysis 367
24.3.1 Cell tracking platforms 367
24.3.2 Recording live cell characteristics 369
24.3.3 Vital biomarkers for mesenchymal stromal cells 370
24.3.4 Mimicking in vivo microenvironments in vitro 373
24.4 Case study: tracking differentiation of endothelial cells from cardiac-derived mesenchymal stromal cells 375
24.4.1 Background and experimental aims 375
24.4.2 Methods 375
24.4.3 Results and discussion 378
24.4.4 Conclusion and future work 380
24.5 Future perspective on live cell imaging and single cell tracking 380
References 382
Chapter 25: The role of mesenchymal stem/stromal cells in angiogenesis 385
25.1 Introduction 385
25.2 The current concept of angiogenesis 385
25.3 Proangiogenic properties of mesenchymal stem/stromal cells 388
25.3.1 The mesenchymal stem/stromal cell secretome: a kaleidoscope of angiogenic molecules 388
25.3.2 The effect of mesenchymal stem/stromal cells on the behavior of endodothelial cells in vitro 390
25.3.3 Mesenchymal stem/stromal cells induce angiogenesis in vivo 392
25.4 Mesenchymal stem/stromal cells as a therapeutic tool for diseases caused by insufficient angiogenesis 393
25.4.1 Peripheral ischemic arterial disease 393
25.4.2 Stroke 393
25.4.3 Myocardial infarction 394
25.4.4 Failure of surface wound healing 395
25.4.5 The dual role of mesenchymal stem/stromal cells in cancer biology 395
25.5 Enhancing the angiogenic efficacy of mesenchymal stem/stromal cells 396
25.6 Transdifferentiation of mesenchymal stem/stromal cells towards endothelial cells 397
25.7 Conclusions, therapeutic expectations, and challenges 397
References 399
Chapter 26: The relationship between mesenchymal stromal cells and endothelial cells 404
26.1 Introduction 404
26.2 Transendothelial migration of mesenchymal stromal cells 404
26.2.1 Mesenchymal stromal cell adhesion to endothelial cells 404
26.2.2 Trans-endothelial migration 407
26.3 Mesenchymal stromal cell-endothelial cell crosstalk in angiogenesis 408
26.3.1 Juxtacrine interactions of mesenchymal stromal cells and endothelial cells 408
26.3.2 Paracrine interactions of mesenchymal stromal cells and endothelial cells 410
26.4 Mesenchymal stromal cell-endothelial cell crosstalk in tumor angiogenesis 411
26.4.1 Stimulation 411
26.4.2 Inhibition 413
26.5 Endothelial differentiation of mesenchymal stromal cells 413
26.6 Development of a biologically active niche through bidirectional endothelial cell-stromal cell crosstalk 416
26.7 Determination of stem cell fate through crosstalk with endothelial cells 418
26.8 Beneficial effects of mesenchymal stromal cell-endothelial cell interactions in some tissue pathologies 420
References 420
Chapter 27: The radioresistance of mesenchymal stromal cells and their potential role in the management of radiation injury 429
27.1 Mesenchymal stromal cells: modulators of hematopoiesis 429
27.2 The response of mesenchymal stromal cells to ionizing radiation 431
27.3 The DNA damage response 432
27.3.1 Sensing damage: DNA damage response initiation 434
27.3.2 Sending an SOS: DNA damage response signal transduction and amplification 434
27.3.3 DNA damage checkpoints 435
27.4 DNA double-strand break repair 436
27.4.1 Nonhomologous end joining 436
27.4.2 Homologous recombination 438
27.4.3 DNA double-strand break repair pathway choice 438
27.5 Apoptosis 438
27.6 Cellular senescence 439
27.7 Stem cells exhibit a mixed response to DNA damage 439
27.8 The DNA damage response of mesenchymal stromal cells 439
27.9 Effects of hypoxia on mesenchymal stromal cell radioresistance 441
27.10 Clinical relevance of mesenchymal stromal cells in radiation injury: two sides to the coin 443
27.10.1 Mesenchymal stromal cells and hematopoietic stem cell transplantation 443
27.10.2 Mesenchymal stromal cells and the tumor microenvironment 444
References 445
Chapter 28: The implications of multipotent mesenchymal stromal cells in tumor biology and therapy 453
28.1 Introduction 453
28.2 Origin and identification of mesenchymal stromal cells in the tumor microenvironment 453
28.3 The migratory capacity of mesenchymal stromal cells 454
28.3.1 Intrinsic migratory properties of mesenchymal stromal cells 454
28.3.2 Stimuli produced by the tumor 454
28.4 Context-dependent role of mesenchymal stromal cells in the tumor microenvironment 455
28.4.1 Hypotheses on context-dependent roles of mesenchymal stromal cells in cancer 455
28.4.2 The tumor-suppressing roles of mesenchymal stromal cells 456
28.4.3 The tumor-promoting roles of mesenchymal stromal cells 456
28.5 The potential immunomodulation by mesenchymal stromal cells in the tumor microenvironment 457
28.5.1 Mesenchymal stromal cells inhibit natural killer cells and macrophages 457
28.5.2 Mesenchymal stromal cells inhibit T cell proliferation 458
28.5.3 Mesenchymal stromal cells promote the expansion and function of regulatory T cells 458
28.5.4 Mesenchymal stromal cells inhibit the function of dendritic cells 458
28.6 Therapeutic application of mesenchymal stromal cells in cancer 458
28.6.1 Potential therapeutic application 458
28.6.2 Reasons for caution 458
Acknowledgments 459
References 459
Chapter 29: Mesenchymal stem/stromal cell therapy: mechanism of action and host response 464
29.1 Mesenchymal stem/stromal cells 464
29.2 Therapeutic application of mesenchymal stem/stromal cells 465
29.3 Mechanism of action 467
29.4 Host immune response to autologous mesenchymal stem/stromal cells transplantation 468
29.5 Mesenchymal stromal cells in an inflammatory microenvironment 468
29.6 Mesenchymal stem/stromal cells-mediated immunomodulation of the innate immune system 470
29.7 Mesenchymal stem/stromal cells-mediated immune modulation of the adaptive immune system 472
29.8 Host immune response to transplantation of allogeneic mesenchymal stem/stromal cells 472
29.9 Summary 473
References 474
Chapter 30: The differences between mesenchymal stromal cells and fibroblasts 479
30.1 Introduction 479
30.2 Phenotypic similarities and differences between mesenchymal stromal cells and fibroblasts 480
30.3 Cell surface membrane markers 480
30.4 Gene expression profile of mesenchymal stromal cells and fibroblasts 481
30.5 Differentiation potential of mesenchymal stromal cells and fibroblasts 483
30.6 Immune modulation capability of mesenchymal stromal cells and fibroblasts 484
30.7 Modulation of inflammation by mesenchymal stromal cells and fibroblasts 486
30.8 Angiogenic properties of mesenchymal stromal cells and fibroblasts 488
30.9 Conclusions 489
References 489
Chapter 31: Derivation of mesenchymal stem/stromal cells from induced pluripotent stem cells 494
31.1 Introduction 494
31.2 Mesenchymal stem/stromal cells as candidates for cellular therapy 495
31.3 Mesenchymal stem/stromal cells 495
31.4 Adult bone-marrow-derived mesenchymal stem/stromal cells 495
31.5 Fetal tissue-derived mesenchymal stem/stromal cells 495
31.6 Embryonic stem cells 496
31.7 Embryonic stem-cell-derived mesenchymal stem/stromal cells 496
31.8 Induced pluripotent stem cells 496
31.9 Small-molecule methods for differentiating pluripotent stem cells into mesenchymal stem/stromal cells 497
31.10 Derivation of induced pluripotent stem cell-mesenchymal stem/stromal cells through a novel transforming growth factor-? inhibitor method 497
31.11 Mesenchymal characterization of induced pluripotent stem cell-mesenchymal stem/stromal cells derived through the inhibitor method 499
31.12 Immune tolerance to induced pluripotent stem cell-mesenchymal stem/stromal cells 499
31.13 Kinetics of the proliferation of induced pluripotent stem cell-mesenchymal stem/stromal cells 499
31.14 Tumorigenic potential of induced pluripotent stem cell-mesenchymal stem/stromal cells 500
31.15 Critical parameters for future preclinical production of induced pluripotent stem cell-mesenchymal stem/stromal cells 500
31.16 Plasticity of lineage commitment: reprogramming, deprogramming and dedifferentiation 500
31.17 How to develop "young" mesenchymal stem/stromal cells: going backward to go forward? 501
31.18 Small-molecules inhibitors for generating ``young´´ stem cells 501
31.19 Primitive stem cells and mesenchymal stem/stromal cell generation by physical factors 501
31.20 Conclusions 501
31.21 Future directions 502
Acknowledgements 502
References 502
Chapter 32: The role of mesenchymal stem cells in hematopoiesis 505
32.1 Introduction 505
32.2 Hematopoietic stem cells need a niche 506
32.3 A mesenchymal hierarchy 506
32.4 Identification of mesenchymal stem cells and their relationship with hematopoietic stem cells in the mouse 507
32.5 More than one nestin cell type and hematopoietic stem cell niche exist in the mouse bone marrow 508
32.6 Controversies surrounding nestin mesenchymal stem cells and other genetic models for alternative mesenchymal stem cells 509
32.7 Other stromal cells regulate hematopoietic stem cells and additional tools to study their role in regulating hematopoiesis 510
32.7.1 Osteoblastic lineage and osteoblasts 511
32.7.2 Endothelial cells 511
32.7.3 Megakaryocytes, Schwann cells, and the transforming growth factor-? connection 512
32.7.4 Adrenergic neurons 513
32.7.5 Macrophages 513
32.8 Human mesenchymal stem cells and human hematopoiesis 514
32.9 Conclusions 515
References 515
Chapter 33: The modulatory effects of mesenchymal stromal cells on the innate immune system 519
33.1 Introduction to the innate immune system 519
33.2 Interactions with dendritic cells 519
33.3 Interactions with monocytes, macrophages, and immature myeloid cells 521
33.4 Interactions with natural killer lymphocytes 522
33.5 Interactions with neutrophils, other granulocytes, and mast cells 523
33.6 Interactions with complement 523
References 524
Chapter 34: The modulatory effects of mesenchymal stromal cells on the adaptive immune system 528
34.1 Introduction to the adaptive immune system 528
34.2 Interactions with T lymphocytes 528
34.3 Interactions with B lymphocytes 530
References 530
Chapter 35: The role of mesenchymal stromal cells in the repair of acute organ injury 534
35.1 Effect of acute organ injury on the proliferative and functional activity of mesenchymal stromal cells 534
35.1.1 The effect of catecholamines on mesenchymal stromal cells 534
35.1.2 The impact of hypoxia as a factor of acute injury on mesenchymal stromal cell proliferation 535
35.1.3 Effect of hypoxia as a factor of acute injury on the paracrine function of mesenchymal stromal cells 536
35.1.4 Effect of tissue-specific proteins released after acute tissue injury on mesenchymal stromal cells 539
35.2 Paracrine effect of mesenchymal stromal cells in acute organ injury 539
35.2.1 Background 539
35.2.2 Paracrine factors secreted by mesenchymal stromal cells 540
35.2.3 Immunosuppressive and anti-inflammatory effects of mesenchymal stromal cells 540
35.2.4 The pro-angiogenic and tissue regenerative effects of mesenchymal stromal cells in acute organ injury 543
35.2.5 The antiapoptotic activity of mesenchymal stromal cells 544
35.2.6 Mesenchymal stromal-cell-derived microvesicles: an essential part of the paracrine mechanism 545
35.3 Mesenchymal-stromal cells in the treatment of acute ischemia-reperfusion injury 546
35.3.1 Ischemia-reperfusion injury pathogenesis 547
35.3.2 The use of mesenchymal stromal cells in kidney ischemia-reperfusion injury 547
35.3.3 Mesenchymal stromal cells and myocardial ischemia-perfusion injury 548
35.3.4 Mesenchymal stromal cells and ischemia-reperfusion injury of other organs 549
35.3.5 Conclusions 549
35.4 The use of mesenchymal stromal cells in acute lung and airway injury 549
35.4.1 Repair of the proximal regions of the airways after acute injury 550
35.5 Current approaches to controlled transplantation of mesenchymal stromal cells in acute organ injury 553
35.6 Conclusions 554
Acknowledgment 555
References 555
Chapter 36: The use of mesenchymal stromal cells in the treatment of diseases of the cornea 562
36.1 Introduction 562
36.2 Anatomy and physiology of the human cornea 567
36.3 Overview of corneal pathology 568
36.3.1 Ocular surface disease 569
36.3.2 Diseases of the corneal stroma and endothelium 569
36.4 Corneal transplantation and cultivated epithelial autografts 570
36.5 Evidence for mesenchymal stromal cells as modulators of corneal disease 571
36.5.1 Immunology of the cornea 571
36.5.2 Immunology of corneal transplantation 572
36.5.3 Immunomodulatory properties of mesenchymal stromal cells 573
36.5.4 Mesenchymal stromal cells as modulators of corneal wound healing and tissue regeneration 573
36.5.5 Mesenchymal stromal cells as modulators of corneal transplantation 574
36.6 Evidence for mesenchymal stromal cells as a source of new corneal cells 575
36.6.1 Mesenchymal stromal cell differentiation into corneal epithelium 575
36.6.2 Mesenchymal stromal cell differentiation into keratocytes 576
36.6.3 Mesenchymal stromal cell differentiation into corneal endothelium 576
36.7 The biology of cornea-derived mesenchymal stromal cells 576
36.8 Conclusions and future directions 578
Acknowledgments 578
References 578
Chapter 37: The role of paracrine factors secreted by mesenchymal stromal cells in acute tissue injury 582
37.1 Introduction 582
37.2 Cell replacement and cell empowerment 582
37.3 Paracrine factors produced by mesenchymal stromal cells 583
37.3.1 Growth factors and mesenchymal-stromal-cell-mediated tissue repair 584
37.3.2 Soluble immunosuppressive factors and mesenchymal-stromal-cell-mediated tissue repair 584
37.3.3 Inducible nitric oxide synthase/indoleamine 2,3-dioxygenase 585
37.3.4 Prostaglandin E2 586
37.3.5 Tumor-necrosis-factor-inducible gene 6 protein 586
37.3.6 Chemokine (C-C motif) ligand 2 586
37.3.7 Interleukin-6 586
37.3.8 Interleukin-10 586
37.3.9 Transforming growth factor-? 587
37.3.10 Human leukocyte antigen G 587
37.3.11 Galectins 587
37.3.12 Other soluble immunosuppressive factors secreted by MSCs 587
37.4 Conclusions 587
Acknowledgments 587
References 587
Chapter 38: Treatment of lung disease by mesenchymal stromal cell extracellular vesicles 591
38.1 Introduction 591
38.2 Definitions and characterization of extracellular vesicles 592
38.3 Nomenclature defined by size and morphology 593
38.4 Common methods of collection of extracellular vesicles 594
38.4.1 Ultracentrifugation 594
38.4.2 Size exclusion 594
38.4.3 Immunoaffinity isolation 594
38.4.4 Polymeric precipitation 594
38.5 Quantification of extracellular vesicles 594
38.5.1 Optical single-particle tracking: nanoparticle tracking analyses 594
38.5.2 Flow cytometry 595
38.5.3 Electron microscopy 595
38.5.4 Protein concentration 595
38.5.5 Cell count 595
38.6 Interaction of extracellular vesicles with targeted cells 595
38.7 Endogenous extracellular vesicles in lung disease 596
38.7.1 Endogenous extracellular vesicles in acute respiratory distress syndrome 596
38.7.2 Endogenous extracellular vesicles in chronic obstructive pulmonary disease 598
38.7.3 Endogenous extracellular vesicles in asthma 599
38.7.4 Endogenous extracellular vesicles as biomarkers in lung disease 599
38.7.5 Endogenous extracellular vesicles as potential therapeutic targets for lung diseases 600
38.8 Therapeutic properties of extracellular vesicles derived from mesenchymal stromal cells 600
38.8.1 Mesenchymal stromal cell vesicles for kidney injury 600
38.8.2 Mesenchymal stromal cell vesicles for cardiac injury 602
38.8.3 Mesenchymal stromal cell vesicles for liver injury 603
38.8.4 Mesenchymal stromal cell vesicles for neural injury 603
38.8.5 Mesenchymal stromal cell vesicles for lung diseases 603
38.9 Remaining questions on the therapeutic use of mesenchymal stromal cell extracellular vesicles 604
38.9.1 Isolation and quantification techniques 604
38.9.2 Extracellular vesicle characterization 604
38.9.3 Feasibility of large-scale generation of extracellular vesicles 604
38.10 Regulatory considerations for the clinical use of extracellular vesicles 604
38.11 Conclusions 604
References 605
Chapter 39: Evaluating mesenchymal stem/stromal cells for treatment of asthma and allergic rhinitis 611
39.1 Summary 611
39.2 Introduction 611
39.3 Early and late asthma response 611
39.4 Airway remodeling 612
39.5 Innate immunity of the airway 612
39.6 Adaptive immunity of the respiratory tract 613
39.7 Toll-like receptors 613
39.8 Allergic rhinitis and immunology 613
39.9 Immune modulation by mesenchymal stem/stromal cells 615
39.10 The future of mesenchymal stem/stromal cells as therapy for allergic diseases 616
References 616
Chapter 40: Stem cell therapies for Huntington's disease 619
40.1 Introduction 619
40.2 Huntington's disease 619
40.2.1 Prevalence and symptomology 620
40.2.2 Neuronal pathology 620
40.2.3 Mechanisms of neurodegeneration 621
40.3 Animal models 622
40.3.1 Transgenic models 622
40.4 In vitro models 622
40.5 Experimental therapies 623
40.6 Cell transplantation 623
40.6.1 Mesenchymal stem/stromal cells 623
40.6.2 Genetic engineering of mesenchymal stem/stromal cells 625
40.6.3 Embryonic and fetal stem cells 626
40.6.4 Neural stem cells 627
40.6.5 Induced pluripotent stem cells 628
40.6.6 Co-transplantation paradigm 631
40.7 Conclusions 631
References 632
Section IV: The role of bioengineering in the therapeutic applications of mesenchymal stromal cells 637
Chapter 41: Endometrial mesenchymal stromal cell and tissue engineering for pelvic organ prolapse repair 639
41.1 Introduction 639
41.2 Pelvic floor disorders 639
41.3 Pelvic organ prolapse 640
41.3.1 Surgical treatment for pelvic organ prolapse 640
41.3.2 New meshes for treatment of pelvic organ prolapse 641
41.4 Tissue engineering 641
41.4.1 Candidate cells for tissue engineering applications for pelvic organ disorders 641
41.5 Endometrium is highly regenerative and contains stem/stromal cells 644
41.5.1 Human endometrial mesenchymal stem/stromal cells 644
41.6 Culture expansion of endometrial mesenchymal stem/stromal cells toward current good manufacturing practice conditions 646
41.7 Tissue engineering for pelvic organ prolapse repair 647
41.7.1 A large animal preclinical model for pelvic organ proplapse 649
41.8 Conclusions 650
Acknowledgments 650
References 650
Chapter 42: Closed automated large-scale bioreactors for manufacturing mesenchymal stromal cells for clinical use 654
42.1 Introduction 654
42.2 Design of a semi-automated closed-system bioreactor capable of manufacturing mesenchymal stromal cells for clinical use 654
42.3 A commercially available closed-system bioreactor for manufacturing mesenchymal stromal cells for clinical use 655
References 656
Section V: GMP manufacturing of mesenchymal stromal cells for clinical use 657
Chapter 43: Current good manufacturing practice for the isolation and ex vivo expansion of mesenchymal stromal cells derived from term human placenta for use in clinical trials 659
43.1 Source of mesenchymal stromal cells for use in clinical trials 659
43.2 Inclusion criteria for mothers wishing to donate their term placenta for isolation and expansion of mesenchymal stromal cells for use in clinical trials approved by a human research ethics committee 660
43.3 Exclusion criteria for mothers wishing to donate their term placenta for isolation and expansion of mesenchymal stromal cells for use in clinical trials approved by a human research ethics committee 660
43.4 Mesenchymal stromal cell manufacturing 661
43.4.1 The good manufacturing process facility 661
43.4.2 Quality control and quality assurance 661
43.4.3 Isolating and expanding mesenchymal stromal cells from human term placenta 661
43.4.4 Testing performed on mesenchymal stromal cells manufactured for clinical use 661
43.5 Phase 1 trials using placenta-derived mesenchymal stromal cells 663
References 665
Chapter 44: A comparison of high-tier regulatory documents pertaining to biologic drugs including mesenchymal stromal cells in Australia, Europe, and the USA using a manual documentary analysis 666
44.1 Introduction 666
44.2 Background 666
44.3 Definitions used by the Australian Therapeutic Goods Administration, the European Medicine Agency, and the US Food and Drug Administration for ``biologicals´´ 667
44.4 Complexity of the area 670
44.5 Analysis of documents 671
44.6 Regulatory science 677
44.7 Interpretation of the analysis of the documents 678
44.8 Conclusions 679
References 679
Section VI: The therapeutic application of mesenchymal stromal cells 683
Chapter 45: The use of mesenchymal stromal cells in acute and chronic heart disease 685
45.1 Introduction 685
45.2 The biology of acute and chronic ischemic cardiomyopathy 685
45.3 Characterization of mesenchymal stromal/stem cells 686
45.3.1 Immunomodulatory properties 687
45.3.2 Antifibrotic effects 688
45.3.3 Cardiomyogenesis in vitro and in vivo 688
45.3.4 Neovascularization 689
45.3.5 Paracrine effects 690
45.3.6 Exosomes 690
45.3.7 Mitochondrial transfer 690
45.3.8 Preconditioning 690
45.3.9 Genetic modification 691
45.4 Cell combination therapy 691
45.5 Clinical trials utilizing bone-marrow-derived mesenchymal stromal/stem cells 692
45.5.1 Acute myocardial infarction 692
45.5.2 Chronic myocardial infarction 693
45.6 Clinical trials utilizing adipose-derived mesenchymal stromal/stem cells 694
45.7 Preconditioning in the clinical setting 695
45.8 Conclusions 695
References 695
Chapter 46: The role of mesenchymal stem/stromal cells in the management of critical limb ischemia 699
46.1 Introduction 699
46.2 Mesenchymal stem/stromal cells and angiogenesis 701
46.3 Potency assays for cells to be used in critical limb ischemia 702
46.3.1 Ixmyelocel-T 702
46.3.2 Stempeucel® 703
46.4 Preclinical studies 703
46.4.1 Preclinical safety studies 703
46.4.2 Preclinical efficacy studies 705
46.5 Clinical trials in critical limb ischemia 705
46.5.1 Safety of mesenchymal stromal cells in clinical trials 705
46.5.2 Efficacy of mesenchymal stromal cells in clinical trials of critical limb ischemia 706
46.5.3 Clinical trials in India 709
46.5.4 Stempeutics research experience in critical limb ischemia 709
46.5.5 Phase I/II study in patients with critical limb ischemia 709
46.5.6 Phase II study in patients with Buerger's disease 711
46.6 Conclusions 711
References 712
Chapter 47: The role of mesenchymal stromal cells in the management of musculoskeletal disorders 715
47.1 Summary 715
47.2 Introduction 715
47.3 Stem cells for bone regeneration 717
47.3.1 Bone defects 717
47.3.2 Osteonecrosis 718
47.3.3 Wear-particle-related osteolysis 719
47.3.4 Systemic bone diseases 719
47.4 Stem cells for cartilage regeneration 720
47.4.1 Osteoarthritis 721
47.5 Stem cells for tendon regeneration 721
47.6 Stem cells for skeletal muscle regeneration 722
47.7 Stem cells for wound repair 723
47.8 Conclusions 723
References 723
Chapter 48: The potential role of bone marrow mesenchymal stromal cells in the treatment of ischemic stroke 728
48.1 Introduction 728
48.1.1 Stroke 728
48.1.2 Stem/stromal cells 729
48.1.3 Mesenchymal stromal cells 729
48.2 Transplantation route and mechanisms of migration 731
48.3 Tracking techniques for transplanted mesenchymal stromal cells 736
48.4 Cytokines and neurotrophic factors 737
48.5 Angiogenesis 737
48.6 Neurogenesis 738
48.7 Axonal sprouting and remyelination 739
48.8 Antiapoptotic effects 739
48.9 Immunomodulation 740
48.10 Pretreatment of mesenchymal stromal cells prior to their administration in animal models of ischemic stroke 740
48.10.1 Administration of genetically engineered mesenchymal stromal cells 742
48.10.2 Administration of mesenchymal stromal cells in combination with chemical agents 742
48.11 Clinical trials involving bone-marrow-derived mesenchymal stromal cells in the treatment of ischemic stroke 743
48.12 Controversies and safety analysis of bone-marrow-derived mesenchymal stromal cells in the treatment of ischemic stroke 744
48.12.1 Conflicting results in animal models 744
48.12.2 Combined transplantation of mesenchymal stromal cells and neural stem/precursor cells 744
48.13 Conclusions and perspectives 745
Acknowledgments 745
References 745
Chapter 49: The role of mesenchymal stromal cells in spinal cord injury 752
49.1 The central nervous system 752
49.2 Spinal cord injury 752
49.3 Cell therapy 753
49.3.1 Mesenchymal stromal cells 754
49.4 Chronic spinal cord injury 759
49.5 Cellular transplants for spinal cord injury 760
49.5.1 Use of hematopoietic stem/progenitor cells for spinal cord injury 760
49.5.2 Use of mesenchymal stromal cells for spinal cord injury 761
49.6 Conclusions 761
Acknowledgments 763
References 763
Chapter 50: The role of mesenchymal stromal cells in the treatment of ulcerative colitis and Crohn's disease 768
50.1 Inflammatory bowel diseases 768
50.2 Pathogenesis of inflammatory bowel diseases 769
50.3 Treatment of Crohn's disease 772
50.3.1 Current treatment options for Crohn's disease 772
50.3.2 Potential treatment options 773
50.4 Treatment of ulcerative colitis 775
50.4.1 Current treatment options for ulcerative colitis 775
50.4.2 Potential new treatment options 775
50.5 Properties of mesenchymal stromal cells 775
50.5.1 Immunomodulation 776
50.5.2 Immune tolerance 777
50.5.3 Tissue regeneration 778
50.5.4 Homing 778
50.5.5 Differentiation and stimulation of tissue repair 778
50.6 Mesenchymal stromal cell administration in inflammatory bowel diseases 778
50.6.1 Mesenchymal stromal cell administration for fistulizing Crohn's disease 779
50.6.2 Autologous mesenchymal stromal cell administration for fistulizing Crohn's disease 779
50.6.3 Allogeneic mesenchymal stromal cell administration for fistulizing Crohn's disease 780
50.6.4 Autologous mesenchymal stromal cell administration for luminal inflammatory bowel diseases 780
50.6.5 Allogeneic mesenchymal stromal cell administration for luminal inflammatory bowel diseases 780
50.7 The future of mesenchymal stromal cell treatment in inflammatory bowel diseases 781
50.7.1 Ongoing protocols 781
50.8 Issues to be resolved 782
50.8.1 Source of mesenchymal stromal cells 782
50.8.2 Autologous versus allogeneic mesenchymal stromal cells 783
50.8.3 Dosage and modalities of administration 783
50.8.4 Concomitant use of other drugs 783
50.9 Safety 783
50.10 Conclusions 783
References 784
Chapter 51: Mesenchymal stromal cells targeting kidney disease: benefits of a combined therapeutic approach 792
51.1 Introduction 792
51.2 Immune modulation and protective effects of mesenchymal stromal cells 792
51.3 Mesenchymal stromal cell homing, recruitment, and tracking 795
51.4 Mechanisms of kidney injury and capacity for repair 797
51.5 Kidney injury and repair in balance with fibrosis 797
51.6 Mesenchymal stromal cells as delivery tools for therapies 798
51.7 Clinical trials with mesenchymal stromal cells 799
51.8 The antifibrotic functions of relaxin 801
51.9 Combination therapy using mesenchymal stromal cells and relaxin 802
51.10 Conclusions 802
References 803
Chapter 52: The biology and potential clinical applications of mesenchymal stromal cells in diseases of the lung 808
52.1 Introduction to lung disease 808
52.1.1 The global burden of lung disease 808
52.1.2 The pathogenesis of lung diseases 808
52.1.3 The range of lung diseases 809
52.2 What are stem cells? 809
52.3 What are mesenchymal stromal cells? 809
52.4 Lung-resident mesenchymal stromal cells 810
52.5 Tracking mesenchymal stromal cells in the body 810
52.6 The properties of mesenchymal stromal cells that favor repair 810
52.6.1 Avoidance of immune recognition 810
52.6.2 Mechanisms of mesenchymal-stromal-cell-mediated immunomodulation 810
52.6.3 Mesenchymal-stromal-cell-mediated repair via trophic factors 813
52.7 Mesenchymal stromal cells as delivery agents for drugs 813
52.7.1 Viral transduction 813
52.7.2 Genetic modulation 814
52.7.3 Nanoparticle incorporation 814
52.7.4 Surface modification 814
52.7.5 Preconditioned mesenchymal stromal cells 814
52.8 Preclinical and clinical studies of mesenchymal stromal cells in pulmonary diseases 814
52.8.1 Idiopathic pulmonary fibrosis 814
52.8.2 Chronic obstructive pulmonary disease 817
52.8.3 Acute lung injury and acute respiratory distress syndrome 818
52.9 Challenges in mesenchymal stromal cell administration in lung diseases 819
52.9.1 Optimal dosage of mesenchymal stromal cells 819
52.9.2 Timing of mesenchymal stromal cell administration 820
52.10 Summary and conclusions 820
References 820
Chapter 53: The role of mesenchymal stromal cells in diseases of the lung 825
53.1 Introduction 825
53.2 Pulmonary fibrosis 825
53.2.1 Animal models 826
53.2.2 Clinical trials of mesenchymal stromal cells 826
53.3 Asthma 826
53.3.1 Preclinical models 828
53.3.2 Clinical trials of mesenchymal stromal cells 828
53.4 Obliterative bronchiolitis 828
53.4.1 Preclinical animal models 828
53.4.2 Clinical trials of mesenchymal stromal cells 829
53.5 Chronic obstructive pulmonary disease and emphysema 829
53.5.1 Preclinical animal models 830
53.5.2 Clinical trials with mesenchymal stromal cells 830
53.6 Bronchopulmonary dysplasia 830
53.6.1 Preclinical animal models 830
53.6.2 Clinical trials using mesenchymal stromal cells 830
53.7 Acute respiratory distress syndrome and acute lung injury 830
53.7.1 Preclinical animal models 831
53.7.2 Clinical trials with mesenchymal stromal cells 831
53.8 Conclusions 831
References 831
Chapter 54: Mesenchymal stromal cells for the treatment of autoimmune diseases 832
54.1 Cell biology of endogenous mesenchymal stromal cells 832
54.1.1 Mesenchymal stromal cells coordinate hematopoietic stem cell development 833
54.1.2 Mesenchymal stromal cells and central tolerance in the bone marrow 833
54.2 Cell biology of mesenchymal stromal cells in culture 834
54.2.1 Mesenchymal stromal cells and B cell immunosuppression 835
54.2.2 Mesenchymal stromal cell and T cell co-culture assays 835
54.3 Immunosuppression: lessons from oncology 835
54.3.1 Programmed death ligand 1 and immunosuppression by tumors 836
54.3.2 Programmed death ligand 1 and immunosuppression by mesenchymal stromal cells 836
54.3.3 Indoleamine 2,3-dioxygenase and immunosuppression by tumors 837
54.3.4 Indoleamine 2,3-dioxygenase and immunosuppression by mesenchymal stromal cells 837
54.4 Mesenchymal stromal cell response to inflammatory signals: licensing and integration 838
54.4.1 Mesenchymal stromal cells and complement 838
54.4.2 Mesenchymal stromal cells and toll-like receptors 839
54.4.3 Interferon-? in the immune response 840
54.4.4 Mesenchymal stromal cells and interferon-? 841
54.4.5 Tumor necrosis factor-? in the immune response 841
54.4.6 Synergy of interferon-? and tumor necrosis factor-? in mesenchymal stromal cells 842
54.5 Strength of signal and integration 842
54.6 Clinical applications of mesenchymal stromal cells for immune-mediated diseases 844
54.6.1 How in vitro data inform assessment of clinical efficacy 844
54.6.2 Random donor, industrial scale 844
54.6.3 Allogeneic mesenchymal stromal cells, low passage 845
54.6.4 Autologous mesenchymal stromal cells for autoimmune diseases 846
54.7 Conclusions and next steps 847
References 847
Chapter 55: The role of mesenchymal stromal cells in bacterial infection 852
55.1 Introduction 852
55.2 Experimental models of bacterial infection and sepsis 853
55.3 Effects of mesenchymal stromal cells on the innate immune response 854
55.4 Effects of mesenchymal stromal cells on the adaptive immune response 857
55.5 Antimicrobial activity of mesenchymal stromal cells 857
55.6 Mesenchymal stromal cells and endothelial/epithelial dysfunction 857
55.7 Mesenchymal stromal cells and effect on organ injury in infection 857
55.8 Mesenchymal stromal cell cytokine and growth factor production 858
55.9 Toll-like receptors and mesenchymal stromal cells 859
55.10 Mesenchymal stromal cell homing 859
55.11 Mesenchymal stromal cell response to oxidative stress 859
55.12 Paracrine effects of mesenchymal stromal cells 859
55.13 Transcriptomic analysis of mesenchymal stromal cell therapy in sepsis 860
55.14 Summary 860
References 860
Chapter 56: The use of mesenchymal stromal cells in solid organ transplantation 863
56.1 Introduction 863
56.2 Potential effects of mesenchymal stromal cells in solid organ transplantation 863
56.3 Immunomodulation 864
56.4 Tissue and organ regeneration 864
56.5 Prevention of ischemia-reperfusion injury 864
56.6 Mesenchymal stromal cell administration in solid organ transplantation 864
56.6.1 Kidney transplantation 864
56.6.2 Liver transplantation 867
56.6.3 Heart transplantation 869
56.6.4 Lung transplantation 869
56.6.5 Pancreas and islet transplantation 869
56.6.6 Bowel transplantation 870
56.7 Conclusions 870
References 870
Chapter 57: The role of mesenchymal stromal cells in allogeneic hematopoietic stem cell transplantation 874
57.1 The immunobiology of allogeneic hematopoietic stem cell transplantation 874
57.1.1 Graft rejection and late marrow failure 874
57.1.2 Graft-versus-host disease 874
57.1.3 The graft-versus-leukemia effect 875
57.1.4 The recipient's response to infection 875
57.2 The immunobiology of mesenchymal stromal cells 875
57.3 The role of mesenchymal stromal cells in the expansion of hematopoietic stem cells 875
57.4 The role of mesenchymal stromal cells in marrow graft rejection 875
57.5 The role of mesenchymal stromal cells in the prevention of acute graft-versus-host disease 876
57.6 The role of mesenchymal cells in the treatment of corticosteroid-refractory acute graft-versus-host disease 876
57.7 The mesenchymal stromal cell exosome: a substitute for the mesenchymal stromal cell? 877
References 877
Chapter 58: The role of mesenchymal stromal cells in the management of skin wounds 879
58.1 Introduction 879
58.2 The wound healing process 879
58.3 The role of mesenchymal stromal cells in the wound healing process 880
58.3.1 Immune modulation 880
58.3.2 Antimicrobial activity 880
58.3.3 Chemotactic and migratory activities 880
58.3.4 Paracrine activity 880
58.3.5 Differentiation 880
58.4 Conclusions and the future 880
References 881
Chapter 59: The role of mesenchymal stromal cells in skin wound healing 883
59.1 Summary 883
59.2 Introduction 883
59.3 The role of bone-marrow-derived mesenchymal stromal cells in wound healing 883
59.4 The role of adipose-tissue-derived mesenchymal stromal cells in wound healing 887
59.5 The role of mesenchymal stromal cells from placental tissues in wound healing 889
59.6 The role of mesenchymal stromal cells from dermal tissue in wound healing 890
59.7 The role of mesenchymal stromal cells from blood in wound healing 891
59.8 Questions and challenges regarding mesenchymal stromal cell administration in wound healing 891
59.9 Conclusions 891
References 891
Section VII: Mesenchymal stromal cells as delivery vehicles for therapeutic agents 895
Chapter 60: The role of mesenchymal stromal cells in human brain tumors 897
60.1 Introduction 897
60.2 Mesenchymal stromal cells in the therapy of human gliomas 898
60.3 Cellular therapy for gliomas 898
60.4 The advantages of mesenchymal stromal cells in clinical use 899
60.5 The rationale for using mesenchymal stromal cells in glioma therapy 899
60.6 Mechanisms underlying mesenchymal stromal cell tropism for gliomas 901
60.7 Strategies to enhance mesenchymal stromal cell homing to gliomas 902
60.8 Types of therapeutic cargo 902
60.8.1 Secreted proteins 902
60.8.2 Prodrug enzymes 903
60.8.3 Replication-competent oncolytic viruses 903
60.8.4 Antibodies 904
60.8.5 Nanoparticles 904
60.9 Delivery routes of mesenchymal stromal cells in clinical applications 904
60.10 Mesenchymal stem cells in the biology of gliomas 905
60.11 Controversy over tumor-associated mesenchymal stromal cells in solid tumors and gliomas 905
60.12 A model of mesenchymal stromal cells in glioma biology 906
60.13 Prospects for clinical use of bone-marrow-derived mesenchymal stromal cells in glioma therapy 906
References 907
Chapter 61: Mesenchymal stromal cells as gene delivery vehicles to treat nonmalignant diseases 911
61.1 Introduction 911
61.2 What are mesenchymal stromal cells? 911
61.3 Genetic modification of mesenchymal stromal cells 912
61.3.1 Safety concerns 912
61.3.2 Choice of vector system 912
61.4 Preclinical models of gene-modified mesenchymal stromal cells: mesenchymal stromal cell migration and survival 913
61.5 Gene-modified mesenchymal stromal cells as immune modulators 915
61.6 Gene-modified mesenchymal stromal cells in skeletal disorders 916
61.7 Gene-modified mesenchymal stromal cells in cardiovascular disease 918
61.8 Gene-modified mesenchymal stromal cells in kidney disease 919
61.9 Gene-modified mesenchymal stromal cells in neurological disease 919
61.10 Gene-modified mesenchymal stromal cells in other nonmalignant diseases 921
61.10.1 Hemophilia 921
61.10.2 Metachromatic leukodystrophy 921
61.10.3 Mucopolysaccharidosis type VII 921
61.10.4 Diabetes mellitus 921
61.11 Conclusions and future directions 921
References 923
Chapter 62: Gene therapy for cancer using mesenchymal stromal cells 930
62.1 Introduction 930
62.1.1 Biological characteristics of mesenchymal stromal cells 930
62.1.2 Immunomodulatory effects of mesenchymal stromal cells on immune cells 931
62.1.3 Tumor homing of mesenchymal stromal cells 931
62.2 Applications of genetically engineered mesenchymal stromal cells for cancer therapy 931
62.2.1 Interferons 931
62.2.2 Interleukins 932
62.2.3 Chemokines 932
62.2.4 Suicide genes 932
62.2.5 Other approaches 932
62.3 Molecular mechanisms of mesenchymal stromal cell accumulation at tumor sites 932
62.3.1 Migratory factors 933
62.3.2 Interactions between mesenchymal stromal cells and endothelial cells 933
62.4 Considerations in the use of genetically engineered mesenchymal stromal cells in cancer therapy 933
62.5 Summary and conclusions 934
References 934
Section VIII: The present and the future 937
Chapter 63: Breaking news 939
63.1 In vitro laboratory studies 939
63.2 Preclinical in vivo animal studies 941
63.3 Clinical trials 946
63.4 Regulatory approval for marketing mesenchymal stromal cell products 947
References 947
Chapter 64: Reconciling the stem cell and paracrine paradigms of mesenchymal stem cell function 950
64.1 Summary 950
64.2 Introduction 950
64.3 The stem cell paradigm revisited 951
64.4 The paracrine paradigm 952
64.4.1 "Mesenchymal stem cell pharmacology": cells are not drug-like 953
64.4.2 Priming to enhance mesenchymal stem cell paracrine action also impacts cell growth and survival 954
64.4.3 Licensing of immunomodulatory activity biases cell differentiation 954
64.5 Modeling mesenchymal stem cell function using lessons learned from immunology 954
64.6 A stem-cell-centric view of mesenchymal stem cells 957
64.7 Closing remarks 958
References 958
Glossary 965
Historical notes 985
Index 987
End User License Agreement 1007