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The Biology and Therapeutic Application of Mesenchymal Cells

Wiley-Blackwellerschienen am01.07.2016
The Biology and Therapeutic Application of Mesenchymal Cells comprehensively describes the cellular and molecular biology of mesenchymal stem cells and mesenchymal stromal cells, describing their therapeutic potential in a wide variety of preclinical models of human diseases and their mechanism of action in these preclinical models. Chapters also discuss the current status of the use of mesenchymal stem and stromal cells in clinical trials in a wide range of human diseases and disorders, for many of which there are limited, or no other, therapeutic avenues.
Provides coverage on both the biology of mesenchymal stem cells and stromal cells, and their therapeutic applications
Describes the therapeutic potential of mesenchymal stem and stromal cells in a wide variety of preclinical models of human diseases and their mechanism of action in these preclinical models
Discusses the current status of mesenchymal stem and stromal cells in clinical trials in a wide range of human diseases and disorders, for many of which there are limited, or no other, therapeutic avenues
Written and edited by leaders in the field

The Biology and Therapeutic Application of Mesenchymal Cells is an invaluable resource for those studying stem cells, cell biology, genetics, gene or cell therapy, or regenerative medicine.


Kerry Atkinson, MBBS MD DTM&H FRCP FRACP, is an Adjunct Professor at the University of Queensland Centre for Clinical Research in Brisbane, Australia, an Adjunct Professor in the Stem Cell Laboratories, Queensland University of Technology at the Translational Research Institute, Brisbane, Queensland, Australia and a Specialist in Internal Medicine at the Salisbury Medical Centre, Brisbane, Queensland, Australia.mehr
Verfügbare Formate

Produkt

KlappentextThe Biology and Therapeutic Application of Mesenchymal Cells comprehensively describes the cellular and molecular biology of mesenchymal stem cells and mesenchymal stromal cells, describing their therapeutic potential in a wide variety of preclinical models of human diseases and their mechanism of action in these preclinical models. Chapters also discuss the current status of the use of mesenchymal stem and stromal cells in clinical trials in a wide range of human diseases and disorders, for many of which there are limited, or no other, therapeutic avenues.
Provides coverage on both the biology of mesenchymal stem cells and stromal cells, and their therapeutic applications
Describes the therapeutic potential of mesenchymal stem and stromal cells in a wide variety of preclinical models of human diseases and their mechanism of action in these preclinical models
Discusses the current status of mesenchymal stem and stromal cells in clinical trials in a wide range of human diseases and disorders, for many of which there are limited, or no other, therapeutic avenues
Written and edited by leaders in the field

The Biology and Therapeutic Application of Mesenchymal Cells is an invaluable resource for those studying stem cells, cell biology, genetics, gene or cell therapy, or regenerative medicine.


Kerry Atkinson, MBBS MD DTM&H FRCP FRACP, is an Adjunct Professor at the University of Queensland Centre for Clinical Research in Brisbane, Australia, an Adjunct Professor in the Stem Cell Laboratories, Queensland University of Technology at the Translational Research Institute, Brisbane, Queensland, Australia and a Specialist in Internal Medicine at the Salisbury Medical Centre, Brisbane, Queensland, Australia.
Details
Weitere ISBN/GTIN9781118907375
ProduktartE-Book
EinbandartE-Book
FormatPDF
Erscheinungsjahr2016
Erscheinungsdatum01.07.2016
Seiten1048 Seiten
SpracheEnglisch
Dateigrösse608670
Artikel-Nr.4796350
Rubriken
Genre9201

Inhalt/Kritik

Inhaltsverzeichnis
1;The biology and therapeutic application of mesenchymal cells;1
2;Contents;11
3;Contributors;29
4;Editor's preface;37
5;Section I: An overview of mesenchymal stem cells and mesenchymal stromal cells;39
5.1;Chapter 1: The mesenchymal stem cell, the mesenchymal stromal cell, and the mesenchymal stromal cell exosome;41
5.1.1;1.1 Nomenclature;41
5.1.2;1.2 The mesenchymal stem cell;41
5.1.3;1.3 The mesenchymal stromal cell;42
5.1.4;1.4 The mesenchymal stromal cell exosome and extracellular vesicles;44
5.1.5;References;45
5.2;Chapter 2: The nomenclature of mesenchymal stem cells and mesenchymal stromal cells;46
5.2.1;2.1 Introduction;46
5.2.2;2.2 Historical perspective;46
5.2.3;2.3 The need for common terminology and definition: the International Society for Cellular Therapy white papers of the mid-2000s;47
5.2.4;2.4 Updating terminology;47
5.2.5;References;48
6;Section II: The isolation and ex vivo expansion of mesenchymal stromal cells;49
6.1;Chapter 3: The isolation and expansion of mesenchymal stromal cells from bone marrow;51
6.1.1;3.1 Introduction;51
6.1.2;3.2 Stem cells;52
6.1.3;3.3 Isolation and characterization of bone marrow mesenchymal stromal cells;52
6.1.3.1;3.3.1 Cell surface markers;53
6.1.3.2;3.3.2 Chemokine receptor display;53
6.1.3.3;3.3.3 Mesodermal differentiation capability;55
6.1.4;3.4 The immunomodulatory properties of mesenchymal stromal cells;55
6.1.5;3.5 The transcriptome of mesenchymal stromal cells;56
6.1.6;References;58
6.2;Chapter 4: The biology and clinical applications of mesenchymal stromal cells derived from human gestational tissues;62
6.2.1;4.1 Introduction;62
6.2.2;4.2 Isolation of placental mesenchymal stromal cells;63
6.2.3;4.3 Characteristics of fetally derived mesenchymal stromal cells isolated from gestational tissues;64
6.2.3.1;4.3.1 Amniotic-membrane-derived mesenchymal stromal cells;64
6.2.3.2;4.3.2 Chorionic-membrane-derived mesenchymal stromal cells;64
6.2.4;4.4 Characteristics of maternally derived mesenchymal stromal cells isolated from gestational tissue (the decidua);65
6.2.5;4.5 Comparison of mesenchymal stromal cells from fetal and maternal tissues isolated from gestational tissues;65
6.2.6;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
6.2.7;4.7 Preclinical mesenchymal stromal cell studies;66
6.2.8;4.8 Clinical applications of placental mesenchymal stromal cells;67
6.2.9;4.9 Manufacturing clinical-grade placenta-derived mesenchymal stromal cells;67
6.2.9.1;4.9.1 Phase 1 clinical trials using unrelated major-histocompatibility-unmatched placenta-derived mesenchymal stromal cells;68
6.2.10;4.10 Conclusions;68
6.2.11;References;68
6.3;Chapter 5: Human placenta-derived mesenchymal stem/stromal cells: fetal and maternal origins and critical parameters for ex vivo expansion;70
6.3.1;5.1 Introduction;70
6.3.2;5.2 Mesenchymal stem/stromal cells: a consensus definition?;70
6.3.3;5.3 Prenatal and perinatal tissue sources of mesenchymal stem/stromal cells;71
6.3.4;5.4 Fetal tissue-derived mesenchymal stem/stromal cells;71
6.3.5;5.5 Placental and adnexal stem and progenitor cells;71
6.3.6;5.6 Comparison of mesenchymal stem/stromal cells from different gestational sources;71
6.3.7;5.7 Consensus classification of human placental mesenchymal stem/stromal cells?;72
6.3.8;5.8 Differentially isolating fetal or maternal mesenchymal stem/stromal cells from term placental villi;72
6.3.9;5.9 Confounding factors for the isolation of fetal placental mesenchymal stem/stromal cells from chorionic villi;72
6.3.10;5.10 Assumptions from the literature: lack of data, specific assays, and specific methodological detail;73
6.3.11;5.11 Methods for determining fetal and maternal mesenchymal stem/stromal cells in a cultured cell population;73
6.3.12;5.12 A novel method to isolate fetal and maternal placental mesenchymal stem/stromal cells;74
6.3.13;5.13 Understanding the maternal origin of the placental mesenchymal stem/stromal cells: the septa;74
6.3.14;5.14 Conclusions and future directions;74
6.3.15;Acknowledgments;75
6.3.16;References;75
7;Section III: The cellular and molecular biology of mesenchymal stromal cells;77
7.1;Chapter 6: Epigenetic regulation of mesenchymal stem/stromal cell growth and multipotentiality;79
7.1.1;6.1 Introduction;79
7.1.2;6.2 Mesenchymal stromal/stem cells;80
7.1.3;6.3 Epigenetics;80
7.1.4;6.4 DNA methylation and histone modifications in mesenchymal stem/stromal cells;83
7.1.5;6.5 Epigenetic regulation of osteogenic differentiation;83
7.1.6;6.6 Epigenetic regulation of adipogenic differentiation;85
7.1.7;6.7 Epigenetic regulation of myogenic differentiation;86
7.1.8;6.8 Epigenetic regulation of chondrogenic differentiation;86
7.1.9;6.9 Epigenetic regulation of mesenchymal stem/stromal cell lifespan and senescence;90
7.1.10;6.10 Regulation of epigenetic modifications in mesenchymal stem/stromal cells for clinical use;90
7.1.11;6.11 Conclusions;90
7.1.12;References;91
7.2;Chapter 7: Biological changes in human mesenchymal stromal cells during monolayer culture;96
7.2.1;7.1 Introduction;96
7.2.2;7.2 Mesenchymal stromal cell isolation from bone marrow;97
7.2.3;7.3 Mesenchymal stromal cell isolation from adipose tissue;98
7.2.4;7.4 Biological characteristics;98
7.2.4.1;7.4.1 Morphology and colony formation;98
7.2.4.2;7.4.2 Growth kinetics;99
7.2.4.3;7.4.3 In vitro multipotency;100
7.2.4.4;7.4.4 Gene expression;100
7.2.4.5;7.4.5 Cell surface marker profile;101
7.2.4.6;7.4.6 Secretory profile;104
7.2.5;7.5 Influences on tissue culture parameters;104
7.2.5.1;7.5.1 Seeding density;104
7.2.5.2;7.5.2 Culture medium and supplementation;105
7.2.5.3;7.5.3 Growth factors;105
7.2.5.4;7.5.4 Xeno-free media;105
7.2.5.5;7.5.5 Platelet-derived supplements;105
7.2.5.6;7.5.6 Serum-free media;106
7.2.5.7;7.5.7 Hypoxia;106
7.2.6;7.6 Implications for basic and clinical research;106
7.2.6.1;7.6.1 Trial disparity;106
7.2.6.2;7.6.2 Alternative culture systems;107
7.2.7;7.7 Conclusions and future directions;108
7.2.8;References;108
7.3;Chapter 8: The effect of three-dimensional aggregates on the biology of mesenchymal stromal cells;113
7.3.1;8.1 Three-dimensional multicellular aggregates;113
7.3.2;8.2 Three-dimensional aggregates of mesenchymal stromal cells;114
7.3.3;8.3 Mechanism of mesenchymal stromal cells self-assembly into three-dimensional aggregates;115
7.3.3.1;8.3.1 Cell-cell contact;115
7.3.3.2;8.3.2 Extracellular matrix and the cytoskeleton;115
7.3.3.3;8.3.3 Mesenchymal stromal cells heterospheroids;116
7.3.4;8.4 Mechanisms of aggregate-mediated mesenchymal stromal cell functional enhancement;116
7.3.4.1;8.4.1 Role of cell adhesion molecules in the fate decision of mesenchymal stromal cell three-dimensional aggregates;117
7.3.4.2;8.4.2 Effects of extracellular matrix, cytoskeleton, and morphology on mesenchymal stromal cell lineage commitment in three-dimensional aggregates;118
7.3.4.3;8.4.3 Role of molecular milieu and hypoxia-inducible factor activation;118
7.3.4.4;8.4.4 Metabolism changes in three-dimensional aggregates of mesenchymal stromal cells;119
7.3.4.5;8.4.5 Enhanced anti-inflammatory properties of three-dimensional aggregates of mesenchymal stromal cells;119
7.3.5;8.5 Bioreactor systems for three-dimensional aggregate production;119
7.3.5.1;8.5.1 Scale-up and dynamics of culture;119
7.3.5.2;8.5.2 Spinner flasks;120
7.3.5.3;8.5.3 Rotary wall vessel;120
7.3.5.4;8.5.4 Rotary orbital system;121
7.3.5.5;8.5.5 Comparison of spinner flask and rotary wall vessel;121
7.3.5.6;8.5.6 Other systems;122
7.3.6;8.6 Transplantation of three-dimensional mesenchymal stromal cell aggregates in preclinical animal models of disease;122
7.3.6.1;8.6.1 Enhanced secretory properties of mesenchymal stromal cells aggregates;122
7.3.6.2;8.6.2 Immunomodulation by mesenchymal stromal cell aggregates;122
7.3.6.3;8.6.3 Enhanced multilineage differentiation of three-dimensional mesenchymal stromal cells aggregates;122
7.3.6.4;8.6.4 Recapitulation of mesenchymal condensation and osteochondral differentiation in bone and cartilage regeneration;124
7.3.7;References;125
7.4;Chapter 9: Cell-cell signaling pathways that regulate mesenchymal stromal cell differentiation;129
7.4.1;9.1 Introduction;129
7.4.2;9.2 Mesenchymal stromal cell signaling is dependent on its type;129
7.4.3;9.3 Identity of bone-marrow-derived mesenchymal stromal cells;130
7.4.4;9.4 Mesenchymal stromal cell signaling in the stem cell niche;131
7.4.5;9.5 Regulation of mesenchymal stromal cell differentiation by the TGF-?/BMP signaling pathway;133
7.4.6;9.6 Regulation of mesenchymal stromal cell differentiation by the Wnt signaling pathway;135
7.4.7;9.7 Conclusions;137
7.4.8;References;137
7.5;Chapter 10: Regulation of mitochondrial transport in mesenchymal stromal cells;142
7.5.1;10.1 Introduction;142
7.5.2;10.2 Intercellular organelle transport;143
7.5.2.1;10.2.1 Intercellular communication;143
7.5.2.2;10.2.2 Mitochondrial biology;143
7.5.2.3;10.2.3 Intercellular mitochondrial transport/mitochondrial donation;143
7.5.3;10.3 Mesenchymal stromal cells as potential mitochondrial donors;145
7.5.3.1;10.3.1 Mechanism of intercellular mitochondrial transport regulation;146
7.5.4;10.4 Strategies to improve mitochondrial delivery to target cells;148
7.5.5;10.5 The road ahead;149
7.5.6;References;149
7.6;Chapter 11: The regulation of adipogenesis from adipose-derived stem/stromal cells;152
7.6.1;11.1 Introduction;152
7.6.2;11.2 Adipose-derived stem/stromal cells;153
7.6.2.1;11.2.1 Preparation and molecular characterization of adipose-derived stem/stromal cells;153
7.6.2.2;11.2.2 Differentiation capacity of adipose-derived stem/stromal cells;154
7.6.3;11.3 Process of adipogenic differentiation from adipose-derived stem/stromal cells;154
7.6.3.1;11.3.1 Adipocyte development program;154
7.6.3.2;11.3.2 Signaling pathways associated with adipogenic differentiation;155
7.6.4;11.4 Regulation of adipogenic differentiation from adipose-derived stem/stromal cells;156
7.6.4.1;11.4.1 Transcriptional regulation;156
7.6.4.2;11.4.2 Epigenetic regulation;157
7.6.4.3;11.4.3 Post-transcriptional regulation;159
7.6.5;11.5 The future;163
7.6.6;References;163
7.7;Chapter 12: Modulation of osteogenic differentiation in mesenchymal stromal cells;169
7.7.1;12.1 Introduction;169
7.7.2;12.2 Biology;170
7.7.2.1;12.2.1 Sources of mesenchymal stromal cells;170
7.7.2.2;12.2.2 Cellular regulation of osteogenic differentiation from mesenchymal stromal cells;170
7.7.2.3;12.2.3 Molecular regulation of osteogenic differentiation from mesenchymal stromal cells;172
7.7.2.4;12.2.4 Factors regulating homing of mesenchymal stromal cells to bone;174
7.7.2.5;12.2.5 In vivo detection and contribution of mesenchymal stromal cells to osteogenesis;175
7.7.2.6;12.2.6 Regulating the immune system for bone formation;176
7.7.3;12.3 Clinical applications of mesenchymal stromal cells in bone disorders;176
7.7.3.1;12.3.1 Bone regeneration;176
7.7.3.2;12.3.2 Osteoarthritis;177
7.7.3.3;12.3.3 Osteogenesis imperfecta;178
7.7.4;12.4 Summary;179
7.7.5;References;179
7.8;Chapter 13: The role of glycogen synthase kinase-3 inhibitors on bone remodeling;186
7.8.1;13.1 Overview of glycogen synthase kinase-3;186
7.8.2;13.2 The response of skeletal cells to glycogen synthase kinase-3 inhibitors in vitro;187
7.8.2.1;13.2.1 Lithium chloride;187
7.8.2.2;13.2.2 SB-216763 and SB-415286;189
7.8.2.3;13.2.3 6-bromoindirubin-3'-oxime;190
7.8.2.4;13.2.4 LY603281-31-8;191
7.8.2.5;13.2.5 CT99021/CHIR99021;191
7.8.2.6;13.2.6 AR28 (AZD2858), AR79, and AZ13282107;192
7.8.3;13.3 Bone anabolism through inhibition of glycogen synthase kinase-3 in vivo;193
7.8.3.1;13.3.1 Functional Wnt/?-catenin responses in Xenopus laevis model systems;194
7.8.3.2;13.3.2 Progenitor cell involvement in bone anabolism in vivo;194
7.8.3.3;13.3.3 Alteration in bone resorption in vivo;196
7.8.4;13.4 Impact of glycogen synthase kinase-3 inhibition in bone disease;197
7.8.4.1;13.4.1 Osteopenia and osteoporosis;197
7.8.4.2;13.4.2 Methotrexate-induced bone loss;198
7.8.4.3;13.4.3 Fracture healing;198
7.8.4.4;13.4.4 Multiple myeloma-associated bone disease;199
7.8.4.5;13.4.5 Periodontal disease;199
7.8.4.6;13.4.6 Clinical findings with lithium;199
7.8.5;13.5 Summary;200
7.8.6;References;201
7.9;Chapter 14: Early molecular events during in vitro chondrogenesis;205
7.9.1;14.1 Introduction;205
7.9.2;14.2 Adult articular cartilage;206
7.9.3;14.3 Developmental chondrogenesis;206
7.9.4;14.4 Molecular aspects of in vivo chondrogenesis;207
7.9.5;14.5 Determinants of in vitro chondrogenesis;209
7.9.6;14.6 Tissue source of mesenchymal stromal cells;209
7.9.6.1;14.6.1 In vitro cell culture;209
7.9.7;14.7 Three-dimensional culture systems and bioscaffolds;210
7.9.8;14.8 Epigenetic changes during early in vitro chondrogenesis;210
7.9.8.1;14.8.1 An introduction to epigenetics;210
7.9.8.2;14.8.2 DNA methylation of the COL2A1 and COL10A1 promoters;211
7.9.8.3;14.8.3 DNA methylation of promoters in other chondrogenesis candidate genes;211
7.9.8.4;14.8.4 Genome-wide map of quantified epigenetic changes during in vitro chondrogenesis of bone marrow mesenchymal stromal cells;212
7.9.8.5;14.8.5 Epigenetics: conclusions;213
7.9.9;14.9 Role of microRNAs during early in vitro chondrogenesis;214
7.9.9.1;14.9.1 An introduction to microRNAs;214
7.9.9.2;14.9.2 Role of miRNA-140 in developmental chondrogenesis;215
7.9.9.3;14.9.3 miR-140 targets identified in vivo and in vitro;216
7.9.9.4;14.9.4 Defining the role of miR-140 during chondrogenic differentiation of mesenchymal stromal cells and dedifferentiation of articular chondrocytes;216
7.9.9.5;14.9.5 Impact of microRNAs other than miR-140 on chondrogenic differentiation of mesenchymal stromal cells;217
7.9.9.6;14.9.6 MicroRNAs in chondrogenesis: conclusions;219
7.9.10;14.10 Early changes in gene expression during in vitro chondrogenesis;220
7.9.10.1;14.10.1 Genes involved in collagen fibrillogenesis;221
7.9.10.2;14.10.2 Genes involved in synthesis of proteoglycans and glygosaminoglycans;221
7.9.10.3;14.10.3 Transcription factor genes;221
7.9.10.4;14.10.4 Genes encoding other important cartilage molecules;222
7.9.10.5;14.10.5 Genes encoding unwanted molecules;222
7.9.10.6;14.10.6 Effect on gene expression of changes in the differentiation cocktail;222
7.9.11;14.11 Conclusions;224
7.9.12;References;224
7.10;Chapter 15: The role of the extracellular matrix in the differentiation of mesenchymal stromal cells;229
7.10.1;15.1 Summary;229
7.10.2;15.2 Multipotency of mesenchymal stromal cells;229
7.10.3;15.3 The extracellular matrix and mesenchymal stromal cell differentiation;230
7.10.3.1;15.3.1 The role of osteopontin in mesenchymal stromal cell differentiation;231
7.10.3.2;15.3.2 Geometric cues in mesenchymal stromal cell differentiation;231
7.10.3.3;15.3.3 Crosstalk between the extracellular matrix and mesenchymal stromal cells;231
7.10.4;15.4 Conclusions and future perspectives;232
7.10.5;Acknowledgments;232
7.10.6;References;232
7.11;Chapter 16: Effects of hypoxic culture on bone marrow multipotent mesenchymal stromal cells: from bench to bedside;234
7.11.1;16.1 Introduction;234
7.11.2;16.2 Multipotent mesenchymal stromal cells;234
7.11.3;16.3 Criteria for defining human multipotent stromal cells;235
7.11.4;16.4 Problems encountered in the clinical application of multipotent mesenchymal stromal cells;235
7.11.5;16.5 The hypoxic niche of multipotent mesenchymal stromal cells;235
7.11.6;16.6 Involvement of hypoxia-inducible factor-1? in hypoxia-mediated effects;236
7.11.7;16.7 Effects of hypoxic culture on glucose metabolism and oxidative stress of multipotent mesenchymal stromal cells;236
7.11.8;16.8 Effects of hypoxic culture on the apoptosis of multipotent mesenchymal stromal cells;237
7.11.9;16.9 Effects of hypoxic culture on expansion and life span of multipotent mesenchymal stromal cells;237
7.11.10;16.10 Effects of hypoxic culture on maintaining self-renewal and differentiation potential of multipotent mesenchymal stromal cells;238
7.11.11;16.11 Differentiation of multipotent mesenchymal stromal cells under hypoxic conditions;238
7.11.12;16.12 Effects of hypoxic culture on secretion of paracrine factors by multipotent mesenchymal stromal cells;239
7.11.13;16.13 Effects of hypoxic culture on engraftment of multipotent mesenchymal stromal cells;240
7.11.14;16.14 Effects of hypoxic culture on allogeneic transplantation of multipotent mesenchymal stromal cells;240
7.11.15;16.15 Conclusions;241
7.11.16;Acknowledgments;241
7.11.17;References;241
7.12;Chapter 17: The role of cyclic tensile strain on osteogenesis and angiogenesis in human mesenchymal stem/stromal cells;246
7.12.1;17.1 Introduction;246
7.12.2;17.2 Applications of tensile strain: an interpretation from physiological stimuli in vivo to bioreactors in vitro;247
7.12.2.1;17.2.1 Uniaxial tensile strain;247
7.12.2.2;17.2.2 Equi-/biaxial tensile strain;248
7.12.3;17.3 Mechanical sensing of mesenchymal stem/stromal cells;249
7.12.3.1;17.3.1 Integrins and the cytoskeleton;249
7.12.3.2;17.3.2 The nucleoskeleton and lamins;250
7.12.3.3;17.3.3 Primary cilia;250
7.12.3.4;17.3.4 Stretch-activated calcium channels;251
7.12.3.5;17.3.5 The glycocalyx;251
7.12.4;17.4 The molecular response of mesenchymal stem/stromal cells to cyclic tensile strain;252
7.12.4.1;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
7.12.4.2;17.4.2 Mesenchymal stem/stromal cell secretomes that induce further responses from other cells;254
7.12.5;17.5 Summary;255
7.12.6;Acknowledgments;255
7.12.7;References;255
7.13;Chapter 18: The evolving concept of mesenchymal stromal cells in regenerative medicine: from cell differentiation to secretome;260
7.13.1;18.1 Mesenchymal stromal cells;260
7.13.2;18.2 The mesenchymal stromal cell secretome;262
7.13.2.1;18.2.1 Concept;262
7.13.2.2;18.2.2 Characterization techniques;262
7.13.3;18.3 The mesenchymal stromal cell secretome in transplantation and regenerative medicine;263
7.13.3.1;18.3.1 Graft-versus-host-disease;263
7.13.3.2;18.3.2 The central nervous system;264
7.13.4;18.4 The peripheral nervous system;267
7.13.5;18.5 Future perspectives;268
7.13.6;References;269
7.14;Chapter 19: The secretome of mesenchymal stem/stromal cells undergoing chondrogenic differentiation and those undergoing osteogenic or adipogenic differentiation;274
7.14.1;19.1 Introduction to protein secretion and the analysis of secretomes;274
7.14.2;19.2 Analysis of mesenchymal stem/stromal cell secretomes using proteomic approaches;275
7.14.2.1;19.2.1 Approaches to obtaining secretome samples;275
7.14.2.2;19.2.2 Experimental strategies for in vitro secretome analysis of mesenchymal stem/stromal cells;275
7.14.3;19.3 Analysis of the secretome of mesenchymal stem/stromal cells undergoing chondrogenesis;280
7.14.4;19.4 Characterization of chondrogenesis markers by secretome analysis;280
7.14.5;19.5 Characterization of osteogenesis markers by secretome analysis;285
7.14.6;19.6 Characterization of adipogenesis markers by secretome analysis;285
7.14.7;19.7 Conclusions and future perspectives;285
7.14.8;References;285
7.15;Chapter 20: Mesenchymal stromal cell extracellular vesicles/exosomes;288
7.15.1;20.1 From cell to secretion to exosome;288
7.15.1.1;20.1.1 Mesenchymal stromal cells;288
7.15.1.2;20.1.2 Cell secretion;289
7.15.1.3;20.1.3 Mesenchymal stromal cell extracellular vesicles as the active therapeutic factor;289
7.15.2;20.2 Extracellular vesicles;289
7.15.2.1;20.2.1 Exosome biology and general functions;290
7.15.3;20.3 The therapeutic use of exosomes;290
7.15.3.1;20.3.1 Mesenchymal stromal cell exosomes;291
7.15.3.2;20.3.2 Characterization of mesenchymal stromal cell exosomes;292
7.15.3.3;20.3.3 The biochemical potential of mesenchymal stromal cell exosomes;292
7.15.3.4;20.3.4 Biochemical potency;293
7.15.3.5;20.3.5 Glycolysis;294
7.15.3.6;20.3.6 Proteasome activity;294
7.15.3.7;20.3.7 Signaling: adenosine signaling;294
7.15.3.8;20.3.8 Inhibition of complement activation;294
7.15.3.9;20.3.9 Restoring homeostasis;294
7.15.3.10;20.3.10 Bioenergetic homeostasis;295
7.15.3.11;20.3.11 Immune homeostasis;295
7.15.4;20.4 The clinical translation of mesenchymal stromal cell exosomes;296
7.15.5;20.5 Conclusions;296
7.15.6;References;296
7.16;Chapter 21: Role of tunneling nanotube crosstalk with distressed cardiomyocytes in controlling the heart repair potential of mesenchymal stromal cells;302
7.16.1;21.1 Introduction;302
7.16.2;21.2 Mesenchymal stromal cells as a promising tool to regenerate damaged heart tissue;302
7.16.2.1;21.2.1 Degenerative cardiac diseases: a major public health problem;302
7.16.2.2;21.2.2 Mesenchymal stromal cells: a promising tool to treat the effects of myocardial infarction;303
7.16.2.3;21.2.3 Mechanisms underlying the regenerative effects of mesenchymal stromal cells;304
7.16.3;21.3 Tunneling nanotubes: a universal route of intercellular communication between distant cells;306
7.16.3.1;21.3.1 Structural diversity of tunneling nanotubes;307
7.16.3.2;21.3.2 Mechanisms and factors involved in tunneling nanotube formation;307
7.16.3.3;21.3.3 The diversity of compounds transferred by tunneling nanotubes and their physiological relevance;309
7.16.4;21.4 Tunneling nanotubes: a novel cell-to cell communication pathway improving the cardiac regenerative properties of mesenchymal stromal cells;311
7.16.4.1;21.4.1 Evidence of tunneling-nanotube-mediated communications between stromal cells and cardiomyocytes;311
7.16.4.2;21.4.2 Tunneling nanotube cell-to-cell communication with mesenchymal stromal cells rejuvenates distressed cardiomyocytes through a progenitor-like state;313
7.16.4.3;21.4.3 Tunneling nanotube cell-to-cell communication with distressed cardiomyocytes stimulates the paracrine repair function of mesenchymal stromal cells;315
7.16.5;21.5 Conclusions;317
7.16.6;References;318
7.17;Chapter 22: The preferential homing of mesenchymal stromal cells to sites of inflammation;324
7.17.1;22.1 Introduction;324
7.17.2;22.2 Molecular mechanisms of migration;325
7.17.2.1;22.2.1 Chemokines;325
7.17.2.2;22.2.2 Integrins;327
7.17.2.3;22.2.3 Toll-like receptors;327
7.17.2.4;22.2.4 Matrix metalloproteinases;328
7.17.2.5;22.2.5 Growth factors;329
7.17.3;22.3 The inflammatory milieu;329
7.17.3.1;22.3.1 Passive migration;329
7.17.3.2;22.3.2 Hypoxia;329
7.17.3.3;22.3.3 Cytokines;330
7.17.3.4;22.3.4 Complement;331
7.17.3.5;22.3.5 Macrophages;332
7.17.4;22.4 Mesenchymal stromal cell extravasation;332
7.17.5;22.5 In vivo migration;332
7.17.5.1;22.5.1 In vivo migration studies;332
7.17.5.2;22.5.2 Controversies surrounding in vivo migration;335
7.17.5.3;22.5.3 Real-time in vivo imaging;339
7.17.6;22.6 Optimizing homing;340
7.17.6.1;22.6.1 Culture conditions;340
7.17.6.2;22.6.2 Pretreatment of mesenchymal stromal cells;341
7.17.6.3;22.6.3 Cell engineering;341
7.17.6.4;22.6.4 The host environment;342
7.17.7;22.7 Conclusions;343
7.17.8;References;344
7.18;Chapter 23: The role of chemokines in mesenchymal stromal cell homing to sites of inflammation, including infarcted myocardium;352
7.18.1;23.1 Summary;352
7.18.2;23.2 Introduction;352
7.18.3;23.3 Homing capacity of mesenchymal stromal cells;353
7.18.4;23.4 Homing ability of mesenchymal stromal cells and their therapeutic effects;354
7.18.5;23.5 Mechanisms of leukocyte trafficking to sites of inflammation;354
7.18.6;23.6 Potential ligands/receptors for mesenchymal stromal cell homing;355
7.18.7;23.7 Chemokine involvement in mesenchymal stromal cell homing;355
7.18.7.1;23.7.1 CCR1 and CCR2 involvement in mesenchymal stromal cell homing;355
7.18.7.2;23.7.2 The CXCR4-SDF-1 axis in mesenchymal stromal cell homing;356
7.18.7.3;23.7.3 Other chemokines;357
7.18.8;23.8 Pretreatment of mesenchymal stromal cells with cytokines and growth factors;357
7.18.9;23.9 Summary and future prospects;357
7.18.10;Acknowledgments;357
7.18.11;References;358
7.19;Chapter 24: Live cell imaging and single cell tracking of mesenchymal stromal cells in vitro;361
7.19.1;24.1 Introduction;361
7.19.2;24.2 Technical considerations;364
7.19.2.1;24.2.1 Equipment, software, and hardware requirements;364
7.19.2.2;24.2.2 Image acquisition parameters;365
7.19.2.3;24.2.3 Image processing;365
7.19.2.4;24.2.4 Data storage;366
7.19.3;24.3 Single cell tracking and analysis;367
7.19.3.1;24.3.1 Cell tracking platforms;367
7.19.3.2;24.3.2 Recording live cell characteristics;369
7.19.3.3;24.3.3 Vital biomarkers for mesenchymal stromal cells;370
7.19.3.4;24.3.4 Mimicking in vivo microenvironments in vitro;373
7.19.4;24.4 Case study: tracking differentiation of endothelial cells from cardiac-derived mesenchymal stromal cells;375
7.19.4.1;24.4.1 Background and experimental aims;375
7.19.4.2;24.4.2 Methods;375
7.19.4.3;24.4.3 Results and discussion;378
7.19.4.4;24.4.4 Conclusion and future work;380
7.19.5;24.5 Future perspective on live cell imaging and single cell tracking;380
7.19.6;References;382
7.20;Chapter 25: The role of mesenchymal stem/stromal cells in angiogenesis;385
7.20.1;25.1 Introduction;385
7.20.2;25.2 The current concept of angiogenesis;385
7.20.3;25.3 Proangiogenic properties of mesenchymal stem/stromal cells;388
7.20.3.1;25.3.1 The mesenchymal stem/stromal cell secretome: a kaleidoscope of angiogenic molecules;388
7.20.3.2;25.3.2 The effect of mesenchymal stem/stromal cells on the behavior of endodothelial cells in vitro;390
7.20.3.3;25.3.3 Mesenchymal stem/stromal cells induce angiogenesis in vivo;392
7.20.4;25.4 Mesenchymal stem/stromal cells as a therapeutic tool for diseases caused by insufficient angiogenesis;393
7.20.4.1;25.4.1 Peripheral ischemic arterial disease;393
7.20.4.2;25.4.2 Stroke;393
7.20.4.3;25.4.3 Myocardial infarction;394
7.20.4.4;25.4.4 Failure of surface wound healing;395
7.20.4.5;25.4.5 The dual role of mesenchymal stem/stromal cells in cancer biology;395
7.20.5;25.5 Enhancing the angiogenic efficacy of mesenchymal stem/stromal cells;396
7.20.6;25.6 Transdifferentiation of mesenchymal stem/stromal cells towards endothelial cells;397
7.20.7;25.7 Conclusions, therapeutic expectations, and challenges;397
7.20.8;References;399
7.21;Chapter 26: The relationship between mesenchymal stromal cells and endothelial cells;404
7.21.1;26.1 Introduction;404
7.21.2;26.2 Transendothelial migration of mesenchymal stromal cells;404
7.21.2.1;26.2.1 Mesenchymal stromal cell adhesion to endothelial cells;404
7.21.2.2;26.2.2 Trans-endothelial migration;407
7.21.3;26.3 Mesenchymal stromal cell-endothelial cell crosstalk in angiogenesis;408
7.21.3.1;26.3.1 Juxtacrine interactions of mesenchymal stromal cells and endothelial cells;408
7.21.3.2;26.3.2 Paracrine interactions of mesenchymal stromal cells and endothelial cells;410
7.21.4;26.4 Mesenchymal stromal cell-endothelial cell crosstalk in tumor angiogenesis;411
7.21.4.1;26.4.1 Stimulation;411
7.21.4.2;26.4.2 Inhibition;413
7.21.5;26.5 Endothelial differentiation of mesenchymal stromal cells;413
7.21.6;26.6 Development of a biologically active niche through bidirectional endothelial cell-stromal cell crosstalk;416
7.21.7;26.7 Determination of stem cell fate through crosstalk with endothelial cells;418
7.21.8;26.8 Beneficial effects of mesenchymal stromal cell-endothelial cell interactions in some tissue pathologies;420
7.21.9;References;420
7.22;Chapter 27: The radioresistance of mesenchymal stromal cells and their potential role in the management of radiation injury;429
7.22.1;27.1 Mesenchymal stromal cells: modulators of hematopoiesis;429
7.22.2;27.2 The response of mesenchymal stromal cells to ionizing radiation;431
7.22.3;27.3 The DNA damage response;432
7.22.3.1;27.3.1 Sensing damage: DNA damage response initiation;434
7.22.3.2;27.3.2 Sending an SOS: DNA damage response signal transduction and amplification;434
7.22.3.3;27.3.3 DNA damage checkpoints;435
7.22.4;27.4 DNA double-strand break repair;436
7.22.4.1;27.4.1 Nonhomologous end joining;436
7.22.4.2;27.4.2 Homologous recombination;438
7.22.4.3;27.4.3 DNA double-strand break repair pathway choice;438
7.22.5;27.5 Apoptosis;438
7.22.6;27.6 Cellular senescence;439
7.22.7;27.7 Stem cells exhibit a mixed response to DNA damage;439
7.22.8;27.8 The DNA damage response of mesenchymal stromal cells;439
7.22.9;27.9 Effects of hypoxia on mesenchymal stromal cell radioresistance;441
7.22.10;27.10 Clinical relevance of mesenchymal stromal cells in radiation injury: two sides to the coin;443
7.22.10.1;27.10.1 Mesenchymal stromal cells and hematopoietic stem cell transplantation;443
7.22.10.2;27.10.2 Mesenchymal stromal cells and the tumor microenvironment;444
7.22.11;References;445
7.23;Chapter 28: The implications of multipotent mesenchymal stromal cells in tumor biology and therapy;453
7.23.1;28.1 Introduction;453
7.23.2;28.2 Origin and identification of mesenchymal stromal cells in the tumor microenvironment;453
7.23.3;28.3 The migratory capacity of mesenchymal stromal cells;454
7.23.3.1;28.3.1 Intrinsic migratory properties of mesenchymal stromal cells;454
7.23.3.2;28.3.2 Stimuli produced by the tumor;454
7.23.4;28.4 Context-dependent role of mesenchymal stromal cells in the tumor microenvironment;455
7.23.4.1;28.4.1 Hypotheses on context-dependent roles of mesenchymal stromal cells in cancer;455
7.23.4.2;28.4.2 The tumor-suppressing roles of mesenchymal stromal cells;456
7.23.4.3;28.4.3 The tumor-promoting roles of mesenchymal stromal cells;456
7.23.5;28.5 The potential immunomodulation by mesenchymal stromal cells in the tumor microenvironment;457
7.23.5.1;28.5.1 Mesenchymal stromal cells inhibit natural killer cells and macrophages;457
7.23.5.2;28.5.2 Mesenchymal stromal cells inhibit T cell proliferation;458
7.23.5.3;28.5.3 Mesenchymal stromal cells promote the expansion and function of regulatory T cells;458
7.23.5.4;28.5.4 Mesenchymal stromal cells inhibit the function of dendritic cells;458
7.23.6;28.6 Therapeutic application of mesenchymal stromal cells in cancer;458
7.23.6.1;28.6.1 Potential therapeutic application;458
7.23.6.2;28.6.2 Reasons for caution;458
7.23.7;Acknowledgments;459
7.23.8;References;459
7.24;Chapter 29: Mesenchymal stem/stromal cell therapy: mechanism of action and host response;464
7.24.1;29.1 Mesenchymal stem/stromal cells;464
7.24.2;29.2 Therapeutic application of mesenchymal stem/stromal cells;465
7.24.3;29.3 Mechanism of action;467
7.24.4;29.4 Host immune response to autologous mesenchymal stem/stromal cells transplantation;468
7.24.5;29.5 Mesenchymal stromal cells in an inflammatory microenvironment;468
7.24.6;29.6 Mesenchymal stem/stromal cells-mediated immunomodulation of the innate immune system;470
7.24.7;29.7 Mesenchymal stem/stromal cells-mediated immune modulation of the adaptive immune system;472
7.24.8;29.8 Host immune response to transplantation of allogeneic mesenchymal stem/stromal cells;472
7.24.9;29.9 Summary;473
7.24.10;References;474
7.25;Chapter 30: The differences between mesenchymal stromal cells and fibroblasts;479
7.25.1;30.1 Introduction;479
7.25.2;30.2 Phenotypic similarities and differences between mesenchymal stromal cells and fibroblasts;480
7.25.3;30.3 Cell surface membrane markers;480
7.25.4;30.4 Gene expression profile of mesenchymal stromal cells and fibroblasts;481
7.25.5;30.5 Differentiation potential of mesenchymal stromal cells and fibroblasts;483
7.25.6;30.6 Immune modulation capability of mesenchymal stromal cells and fibroblasts;484
7.25.7;30.7 Modulation of inflammation by mesenchymal stromal cells and fibroblasts;486
7.25.8;30.8 Angiogenic properties of mesenchymal stromal cells and fibroblasts;488
7.25.9;30.9 Conclusions;489
7.25.10;References;489
7.26;Chapter 31: Derivation of mesenchymal stem/stromal cells from induced pluripotent stem cells;494
7.26.1;31.1 Introduction;494
7.26.2;31.2 Mesenchymal stem/stromal cells as candidates for cellular therapy;495
7.26.3;31.3 Mesenchymal stem/stromal cells;495
7.26.4;31.4 Adult bone-marrow-derived mesenchymal stem/stromal cells;495
7.26.5;31.5 Fetal tissue-derived mesenchymal stem/stromal cells;495
7.26.6;31.6 Embryonic stem cells;496
7.26.7;31.7 Embryonic stem-cell-derived mesenchymal stem/stromal cells;496
7.26.8;31.8 Induced pluripotent stem cells;496
7.26.9;31.9 Small-molecule methods for differentiating pluripotent stem cells into mesenchymal stem/stromal cells;497
7.26.10;31.10 Derivation of induced pluripotent stem cell-mesenchymal stem/stromal cells through a novel transforming growth factor-? inhibitor method;497
7.26.11;31.11 Mesenchymal characterization of induced pluripotent stem cell-mesenchymal stem/stromal cells derived through the inhibitor method;499
7.26.12;31.12 Immune tolerance to induced pluripotent stem cell-mesenchymal stem/stromal cells;499
7.26.13;31.13 Kinetics of the proliferation of induced pluripotent stem cell-mesenchymal stem/stromal cells;499
7.26.14;31.14 Tumorigenic potential of induced pluripotent stem cell-mesenchymal stem/stromal cells;500
7.26.15;31.15 Critical parameters for future preclinical production of induced pluripotent stem cell-mesenchymal stem/stromal cells;500
7.26.16;31.16 Plasticity of lineage commitment: reprogramming, deprogramming and dedifferentiation;500
7.26.17;31.17 How to develop "young" mesenchymal stem/stromal cells: going backward to go forward?;501
7.26.18;31.18 Small-molecules inhibitors for generating ``young´´ stem cells;501
7.26.19;31.19 Primitive stem cells and mesenchymal stem/stromal cell generation by physical factors;501
7.26.20;31.20 Conclusions;501
7.26.21;31.21 Future directions;502
7.26.22;Acknowledgements;502
7.26.23;References;502
7.27;Chapter 32: The role of mesenchymal stem cells in hematopoiesis;505
7.27.1;32.1 Introduction;505
7.27.2;32.2 Hematopoietic stem cells need a niche;506
7.27.3;32.3 A mesenchymal hierarchy;506
7.27.4;32.4 Identification of mesenchymal stem cells and their relationship with hematopoietic stem cells in the mouse;507
7.27.5;32.5 More than one nestin cell type and hematopoietic stem cell niche exist in the mouse bone marrow;508
7.27.6;32.6 Controversies surrounding nestin mesenchymal stem cells and other genetic models for alternative mesenchymal stem cells;509
7.27.7;32.7 Other stromal cells regulate hematopoietic stem cells and additional tools to study their role in regulating hematopoiesis;510
7.27.7.1;32.7.1 Osteoblastic lineage and osteoblasts;511
7.27.7.2;32.7.2 Endothelial cells;511
7.27.7.3;32.7.3 Megakaryocytes, Schwann cells, and the transforming growth factor-? connection;512
7.27.7.4;32.7.4 Adrenergic neurons;513
7.27.7.5;32.7.5 Macrophages;513
7.27.8;32.8 Human mesenchymal stem cells and human hematopoiesis;514
7.27.9;32.9 Conclusions;515
7.27.10;References;515
7.28;Chapter 33: The modulatory effects of mesenchymal stromal cells on the innate immune system;519
7.28.1;33.1 Introduction to the innate immune system;519
7.28.2;33.2 Interactions with dendritic cells;519
7.28.3;33.3 Interactions with monocytes, macrophages, and immature myeloid cells;521
7.28.4;33.4 Interactions with natural killer lymphocytes;522
7.28.5;33.5 Interactions with neutrophils, other granulocytes, and mast cells;523
7.28.6;33.6 Interactions with complement;523
7.28.7;References;524
7.29;Chapter 34: The modulatory effects of mesenchymal stromal cells on the adaptive immune system;528
7.29.1;34.1 Introduction to the adaptive immune system;528
7.29.2;34.2 Interactions with T lymphocytes;528
7.29.3;34.3 Interactions with B lymphocytes;530
7.29.4;References;530
7.30;Chapter 35: The role of mesenchymal stromal cells in the repair of acute organ injury;534
7.30.1;35.1 Effect of acute organ injury on the proliferative and functional activity of mesenchymal stromal cells;534
7.30.1.1;35.1.1 The effect of catecholamines on mesenchymal stromal cells;534
7.30.1.2;35.1.2 The impact of hypoxia as a factor of acute injury on mesenchymal stromal cell proliferation;535
7.30.1.3;35.1.3 Effect of hypoxia as a factor of acute injury on the paracrine function of mesenchymal stromal cells;536
7.30.1.4;35.1.4 Effect of tissue-specific proteins released after acute tissue injury on mesenchymal stromal cells;539
7.30.2;35.2 Paracrine effect of mesenchymal stromal cells in acute organ injury;539
7.30.2.1;35.2.1 Background;539
7.30.2.2;35.2.2 Paracrine factors secreted by mesenchymal stromal cells;540
7.30.2.3;35.2.3 Immunosuppressive and anti-inflammatory effects of mesenchymal stromal cells;540
7.30.2.4;35.2.4 The pro-angiogenic and tissue regenerative effects of mesenchymal stromal cells in acute organ injury;543
7.30.2.5;35.2.5 The antiapoptotic activity of mesenchymal stromal cells;544
7.30.2.6;35.2.6 Mesenchymal stromal-cell-derived microvesicles: an essential part of the paracrine mechanism;545
7.30.3;35.3 Mesenchymal-stromal cells in the treatment of acute ischemia-reperfusion injury;546
7.30.3.1;35.3.1 Ischemia-reperfusion injury pathogenesis;547
7.30.3.2;35.3.2 The use of mesenchymal stromal cells in kidney ischemia-reperfusion injury;547
7.30.3.3;35.3.3 Mesenchymal stromal cells and myocardial ischemia-perfusion injury;548
7.30.3.4;35.3.4 Mesenchymal stromal cells and ischemia-reperfusion injury of other organs;549
7.30.3.5;35.3.5 Conclusions;549
7.30.4;35.4 The use of mesenchymal stromal cells in acute lung and airway injury;549
7.30.4.1;35.4.1 Repair of the proximal regions of the airways after acute injury;550
7.30.5;35.5 Current approaches to controlled transplantation of mesenchymal stromal cells in acute organ injury;553
7.30.6;35.6 Conclusions;554
7.30.7;Acknowledgment;555
7.30.8;References;555
7.31;Chapter 36: The use of mesenchymal stromal cells in the treatment of diseases of the cornea;562
7.31.1;36.1 Introduction;562
7.31.2;36.2 Anatomy and physiology of the human cornea;567
7.31.3;36.3 Overview of corneal pathology;568
7.31.3.1;36.3.1 Ocular surface disease;569
7.31.3.2;36.3.2 Diseases of the corneal stroma and endothelium;569
7.31.4;36.4 Corneal transplantation and cultivated epithelial autografts;570
7.31.5;36.5 Evidence for mesenchymal stromal cells as modulators of corneal disease;571
7.31.5.1;36.5.1 Immunology of the cornea;571
7.31.5.2;36.5.2 Immunology of corneal transplantation;572
7.31.5.3;36.5.3 Immunomodulatory properties of mesenchymal stromal cells;573
7.31.5.4;36.5.4 Mesenchymal stromal cells as modulators of corneal wound healing and tissue regeneration;573
7.31.5.5;36.5.5 Mesenchymal stromal cells as modulators of corneal transplantation;574
7.31.6;36.6 Evidence for mesenchymal stromal cells as a source of new corneal cells;575
7.31.6.1;36.6.1 Mesenchymal stromal cell differentiation into corneal epithelium;575
7.31.6.2;36.6.2 Mesenchymal stromal cell differentiation into keratocytes;576
7.31.6.3;36.6.3 Mesenchymal stromal cell differentiation into corneal endothelium;576
7.31.7;36.7 The biology of cornea-derived mesenchymal stromal cells;576
7.31.8;36.8 Conclusions and future directions;578
7.31.9;Acknowledgments;578
7.31.10;References;578
7.32;Chapter 37: The role of paracrine factors secreted by mesenchymal stromal cells in acute tissue injury;582
7.32.1;37.1 Introduction;582
7.32.2;37.2 Cell replacement and cell empowerment;582
7.32.3;37.3 Paracrine factors produced by mesenchymal stromal cells;583
7.32.3.1;37.3.1 Growth factors and mesenchymal-stromal-cell-mediated tissue repair;584
7.32.3.2;37.3.2 Soluble immunosuppressive factors and mesenchymal-stromal-cell-mediated tissue repair;584
7.32.3.3;37.3.3 Inducible nitric oxide synthase/indoleamine 2,3-dioxygenase;585
7.32.3.4;37.3.4 Prostaglandin E2;586
7.32.3.5;37.3.5 Tumor-necrosis-factor-inducible gene 6 protein;586
7.32.3.6;37.3.6 Chemokine (C-C motif) ligand 2;586
7.32.3.7;37.3.7 Interleukin-6;586
7.32.3.8;37.3.8 Interleukin-10;586
7.32.3.9;37.3.9 Transforming growth factor-?;587
7.32.3.10;37.3.10 Human leukocyte antigen G;587
7.32.3.11;37.3.11 Galectins;587
7.32.3.12;37.3.12 Other soluble immunosuppressive factors secreted by MSCs;587
7.32.4;37.4 Conclusions;587
7.32.5;Acknowledgments;587
7.32.6;References;587
7.33;Chapter 38: Treatment of lung disease by mesenchymal stromal cell extracellular vesicles;591
7.33.1;38.1 Introduction;591
7.33.2;38.2 Definitions and characterization of extracellular vesicles;592
7.33.3;38.3 Nomenclature defined by size and morphology;593
7.33.4;38.4 Common methods of collection of extracellular vesicles;594
7.33.4.1;38.4.1 Ultracentrifugation;594
7.33.4.2;38.4.2 Size exclusion;594
7.33.4.3;38.4.3 Immunoaffinity isolation;594
7.33.4.4;38.4.4 Polymeric precipitation;594
7.33.5;38.5 Quantification of extracellular vesicles;594
7.33.5.1;38.5.1 Optical single-particle tracking: nanoparticle tracking analyses;594
7.33.5.2;38.5.2 Flow cytometry;595
7.33.5.3;38.5.3 Electron microscopy;595
7.33.5.4;38.5.4 Protein concentration;595
7.33.5.5;38.5.5 Cell count;595
7.33.6;38.6 Interaction of extracellular vesicles with targeted cells;595
7.33.7;38.7 Endogenous extracellular vesicles in lung disease;596
7.33.7.1;38.7.1 Endogenous extracellular vesicles in acute respiratory distress syndrome;596
7.33.7.2;38.7.2 Endogenous extracellular vesicles in chronic obstructive pulmonary disease;598
7.33.7.3;38.7.3 Endogenous extracellular vesicles in asthma;599
7.33.7.4;38.7.4 Endogenous extracellular vesicles as biomarkers in lung disease;599
7.33.7.5;38.7.5 Endogenous extracellular vesicles as potential therapeutic targets for lung diseases;600
7.33.8;38.8 Therapeutic properties of extracellular vesicles derived from mesenchymal stromal cells;600
7.33.8.1;38.8.1 Mesenchymal stromal cell vesicles for kidney injury;600
7.33.8.2;38.8.2 Mesenchymal stromal cell vesicles for cardiac injury;602
7.33.8.3;38.8.3 Mesenchymal stromal cell vesicles for liver injury;603
7.33.8.4;38.8.4 Mesenchymal stromal cell vesicles for neural injury;603
7.33.8.5;38.8.5 Mesenchymal stromal cell vesicles for lung diseases;603
7.33.9;38.9 Remaining questions on the therapeutic use of mesenchymal stromal cell extracellular vesicles;604
7.33.9.1;38.9.1 Isolation and quantification techniques;604
7.33.9.2;38.9.2 Extracellular vesicle characterization;604
7.33.9.3;38.9.3 Feasibility of large-scale generation of extracellular vesicles;604
7.33.10;38.10 Regulatory considerations for the clinical use of extracellular vesicles;604
7.33.11;38.11 Conclusions;604
7.33.12;References;605
7.34;Chapter 39: Evaluating mesenchymal stem/stromal cells for treatment of asthma and allergic rhinitis;611
7.34.1;39.1 Summary;611
7.34.2;39.2 Introduction;611
7.34.3;39.3 Early and late asthma response;611
7.34.4;39.4 Airway remodeling;612
7.34.5;39.5 Innate immunity of the airway;612
7.34.6;39.6 Adaptive immunity of the respiratory tract;613
7.34.7;39.7 Toll-like receptors;613
7.34.8;39.8 Allergic rhinitis and immunology;613
7.34.9;39.9 Immune modulation by mesenchymal stem/stromal cells;615
7.34.10;39.10 The future of mesenchymal stem/stromal cells as therapy for allergic diseases;616
7.34.11;References;616
7.35;Chapter 40: Stem cell therapies for Huntington's disease;619
7.35.1;40.1 Introduction;619
7.35.2;40.2 Huntington's disease;619
7.35.2.1;40.2.1 Prevalence and symptomology;620
7.35.2.2;40.2.2 Neuronal pathology;620
7.35.2.3;40.2.3 Mechanisms of neurodegeneration;621
7.35.3;40.3 Animal models;622
7.35.3.1;40.3.1 Transgenic models;622
7.35.4;40.4 In vitro models;622
7.35.5;40.5 Experimental therapies;623
7.35.6;40.6 Cell transplantation;623
7.35.6.1;40.6.1 Mesenchymal stem/stromal cells;623
7.35.6.2;40.6.2 Genetic engineering of mesenchymal stem/stromal cells;625
7.35.6.3;40.6.3 Embryonic and fetal stem cells;626
7.35.6.4;40.6.4 Neural stem cells;627
7.35.6.5;40.6.5 Induced pluripotent stem cells;628
7.35.6.6;40.6.6 Co-transplantation paradigm;631
7.35.7;40.7 Conclusions;631
7.35.8;References;632
8;Section IV: The role of bioengineering in the therapeutic applications of mesenchymal stromal cells;637
8.1;Chapter 41: Endometrial mesenchymal stromal cell and tissue engineering for pelvic organ prolapse repair;639
8.1.1;41.1 Introduction;639
8.1.2;41.2 Pelvic floor disorders;639
8.1.3;41.3 Pelvic organ prolapse;640
8.1.3.1;41.3.1 Surgical treatment for pelvic organ prolapse;640
8.1.3.2;41.3.2 New meshes for treatment of pelvic organ prolapse;641
8.1.4;41.4 Tissue engineering;641
8.1.4.1;41.4.1 Candidate cells for tissue engineering applications for pelvic organ disorders;641
8.1.5;41.5 Endometrium is highly regenerative and contains stem/stromal cells;644
8.1.5.1;41.5.1 Human endometrial mesenchymal stem/stromal cells;644
8.1.6;41.6 Culture expansion of endometrial mesenchymal stem/stromal cells toward current good manufacturing practice conditions;646
8.1.7;41.7 Tissue engineering for pelvic organ prolapse repair;647
8.1.7.1;41.7.1 A large animal preclinical model for pelvic organ proplapse;649
8.1.8;41.8 Conclusions;650
8.1.9;Acknowledgments;650
8.1.10;References;650
8.2;Chapter 42: Closed automated large-scale bioreactors for manufacturing mesenchymal stromal cells for clinical use;654
8.2.1;42.1 Introduction;654
8.2.2;42.2 Design of a semi-automated closed-system bioreactor capable of manufacturing mesenchymal stromal cells for clinical use;654
8.2.3;42.3 A commercially available closed-system bioreactor for manufacturing mesenchymal stromal cells for clinical use;655
8.2.4;References;656
9;Section V: GMP manufacturing of mesenchymal stromal cells for clinical use;657
9.1;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
9.1.1;43.1 Source of mesenchymal stromal cells for use in clinical trials;659
9.1.2;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
9.1.3;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
9.1.4;43.4 Mesenchymal stromal cell manufacturing;661
9.1.4.1;43.4.1 The good manufacturing process facility;661
9.1.4.2;43.4.2 Quality control and quality assurance;661
9.1.4.3;43.4.3 Isolating and expanding mesenchymal stromal cells from human term placenta;661
9.1.4.4;43.4.4 Testing performed on mesenchymal stromal cells manufactured for clinical use;661
9.1.5;43.5 Phase 1 trials using placenta-derived mesenchymal stromal cells;663
9.1.6;References;665
9.2;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
9.2.1;44.1 Introduction;666
9.2.2;44.2 Background;666
9.2.3;44.3 Definitions used by the Australian Therapeutic Goods Administration, the European Medicine Agency, and the US Food and Drug Administration for ``biologicals´´;667
9.2.4;44.4 Complexity of the area;670
9.2.5;44.5 Analysis of documents;671
9.2.6;44.6 Regulatory science;677
9.2.7;44.7 Interpretation of the analysis of the documents;678
9.2.8;44.8 Conclusions;679
9.2.9;References;679
10;Section VI: The therapeutic application of mesenchymal stromal cells;683
10.1;Chapter 45: The use of mesenchymal stromal cells in acute and chronic heart disease;685
10.1.1;45.1 Introduction;685
10.1.2;45.2 The biology of acute and chronic ischemic cardiomyopathy;685
10.1.3;45.3 Characterization of mesenchymal stromal/stem cells;686
10.1.3.1;45.3.1 Immunomodulatory properties;687
10.1.3.2;45.3.2 Antifibrotic effects;688
10.1.3.3;45.3.3 Cardiomyogenesis in vitro and in vivo;688
10.1.3.4;45.3.4 Neovascularization;689
10.1.3.5;45.3.5 Paracrine effects;690
10.1.3.6;45.3.6 Exosomes;690
10.1.3.7;45.3.7 Mitochondrial transfer;690
10.1.3.8;45.3.8 Preconditioning;690
10.1.3.9;45.3.9 Genetic modification;691
10.1.4;45.4 Cell combination therapy;691
10.1.5;45.5 Clinical trials utilizing bone-marrow-derived mesenchymal stromal/stem cells;692
10.1.5.1;45.5.1 Acute myocardial infarction;692
10.1.5.2;45.5.2 Chronic myocardial infarction;693
10.1.6;45.6 Clinical trials utilizing adipose-derived mesenchymal stromal/stem cells;694
10.1.7;45.7 Preconditioning in the clinical setting;695
10.1.8;45.8 Conclusions;695
10.1.9;References;695
10.2;Chapter 46: The role of mesenchymal stem/stromal cells in the management of critical limb ischemia;699
10.2.1;46.1 Introduction;699
10.2.2;46.2 Mesenchymal stem/stromal cells and angiogenesis;701
10.2.3;46.3 Potency assays for cells to be used in critical limb ischemia;702
10.2.3.1;46.3.1 Ixmyelocel-T;702
10.2.3.2;46.3.2 Stempeucel®;703
10.2.4;46.4 Preclinical studies;703
10.2.4.1;46.4.1 Preclinical safety studies;703
10.2.4.2;46.4.2 Preclinical efficacy studies;705
10.2.5;46.5 Clinical trials in critical limb ischemia;705
10.2.5.1;46.5.1 Safety of mesenchymal stromal cells in clinical trials;705
10.2.5.2;46.5.2 Efficacy of mesenchymal stromal cells in clinical trials of critical limb ischemia;706
10.2.5.3;46.5.3 Clinical trials in India;709
10.2.5.4;46.5.4 Stempeutics research experience in critical limb ischemia;709
10.2.5.5;46.5.5 Phase I/II study in patients with critical limb ischemia;709
10.2.5.6;46.5.6 Phase II study in patients with Buerger's disease;711
10.2.6;46.6 Conclusions;711
10.2.7;References;712
10.3;Chapter 47: The role of mesenchymal stromal cells in the management of musculoskeletal disorders;715
10.3.1;47.1 Summary;715
10.3.2;47.2 Introduction;715
10.3.3;47.3 Stem cells for bone regeneration;717
10.3.3.1;47.3.1 Bone defects;717
10.3.3.2;47.3.2 Osteonecrosis;718
10.3.3.3;47.3.3 Wear-particle-related osteolysis;719
10.3.3.4;47.3.4 Systemic bone diseases;719
10.3.4;47.4 Stem cells for cartilage regeneration;720
10.3.4.1;47.4.1 Osteoarthritis;721
10.3.5;47.5 Stem cells for tendon regeneration;721
10.3.6;47.6 Stem cells for skeletal muscle regeneration;722
10.3.7;47.7 Stem cells for wound repair;723
10.3.8;47.8 Conclusions;723
10.3.9;References;723
10.4;Chapter 48: The potential role of bone marrow mesenchymal stromal cells in the treatment of ischemic stroke;728
10.4.1;48.1 Introduction;728
10.4.1.1;48.1.1 Stroke;728
10.4.1.2;48.1.2 Stem/stromal cells;729
10.4.1.3;48.1.3 Mesenchymal stromal cells;729
10.4.2;48.2 Transplantation route and mechanisms of migration;731
10.4.3;48.3 Tracking techniques for transplanted mesenchymal stromal cells;736
10.4.4;48.4 Cytokines and neurotrophic factors;737
10.4.5;48.5 Angiogenesis;737
10.4.6;48.6 Neurogenesis;738
10.4.7;48.7 Axonal sprouting and remyelination;739
10.4.8;48.8 Antiapoptotic effects;739
10.4.9;48.9 Immunomodulation;740
10.4.10;48.10 Pretreatment of mesenchymal stromal cells prior to their administration in animal models of ischemic stroke;740
10.4.10.1;48.10.1 Administration of genetically engineered mesenchymal stromal cells;742
10.4.10.2;48.10.2 Administration of mesenchymal stromal cells in combination with chemical agents;742
10.4.11;48.11 Clinical trials involving bone-marrow-derived mesenchymal stromal cells in the treatment of ischemic stroke;743
10.4.12;48.12 Controversies and safety analysis of bone-marrow-derived mesenchymal stromal cells in the treatment of ischemic stroke;744
10.4.12.1;48.12.1 Conflicting results in animal models;744
10.4.12.2;48.12.2 Combined transplantation of mesenchymal stromal cells and neural stem/precursor cells;744
10.4.13;48.13 Conclusions and perspectives;745
10.4.14;Acknowledgments;745
10.4.15;References;745
10.5;Chapter 49: The role of mesenchymal stromal cells in spinal cord injury;752
10.5.1;49.1 The central nervous system;752
10.5.2;49.2 Spinal cord injury;752
10.5.3;49.3 Cell therapy;753
10.5.3.1;49.3.1 Mesenchymal stromal cells;754
10.5.4;49.4 Chronic spinal cord injury;759
10.5.5;49.5 Cellular transplants for spinal cord injury;760
10.5.5.1;49.5.1 Use of hematopoietic stem/progenitor cells for spinal cord injury;760
10.5.5.2;49.5.2 Use of mesenchymal stromal cells for spinal cord injury;761
10.5.6;49.6 Conclusions;761
10.5.7;Acknowledgments;763
10.5.8;References;763
10.6;Chapter 50: The role of mesenchymal stromal cells in the treatment of ulcerative colitis and Crohn's disease;768
10.6.1;50.1 Inflammatory bowel diseases;768
10.6.2;50.2 Pathogenesis of inflammatory bowel diseases;769
10.6.3;50.3 Treatment of Crohn's disease;772
10.6.3.1;50.3.1 Current treatment options for Crohn's disease;772
10.6.3.2;50.3.2 Potential treatment options;773
10.6.4;50.4 Treatment of ulcerative colitis;775
10.6.4.1;50.4.1 Current treatment options for ulcerative colitis;775
10.6.4.2;50.4.2 Potential new treatment options;775
10.6.5;50.5 Properties of mesenchymal stromal cells;775
10.6.5.1;50.5.1 Immunomodulation;776
10.6.5.2;50.5.2 Immune tolerance;777
10.6.5.3;50.5.3 Tissue regeneration;778
10.6.5.4;50.5.4 Homing;778
10.6.5.5;50.5.5 Differentiation and stimulation of tissue repair;778
10.6.6;50.6 Mesenchymal stromal cell administration in inflammatory bowel diseases;778
10.6.6.1;50.6.1 Mesenchymal stromal cell administration for fistulizing Crohn's disease;779
10.6.6.2;50.6.2 Autologous mesenchymal stromal cell administration for fistulizing Crohn's disease;779
10.6.6.3;50.6.3 Allogeneic mesenchymal stromal cell administration for fistulizing Crohn's disease;780
10.6.6.4;50.6.4 Autologous mesenchymal stromal cell administration for luminal inflammatory bowel diseases;780
10.6.6.5;50.6.5 Allogeneic mesenchymal stromal cell administration for luminal inflammatory bowel diseases;780
10.6.7;50.7 The future of mesenchymal stromal cell treatment in inflammatory bowel diseases;781
10.6.7.1;50.7.1 Ongoing protocols;781
10.6.8;50.8 Issues to be resolved;782
10.6.8.1;50.8.1 Source of mesenchymal stromal cells;782
10.6.8.2;50.8.2 Autologous versus allogeneic mesenchymal stromal cells;783
10.6.8.3;50.8.3 Dosage and modalities of administration;783
10.6.8.4;50.8.4 Concomitant use of other drugs;783
10.6.9;50.9 Safety;783
10.6.10;50.10 Conclusions;783
10.6.11;References;784
10.7;Chapter 51: Mesenchymal stromal cells targeting kidney disease: benefits of a combined therapeutic approach;792
10.7.1;51.1 Introduction;792
10.7.2;51.2 Immune modulation and protective effects of mesenchymal stromal cells;792
10.7.3;51.3 Mesenchymal stromal cell homing, recruitment, and tracking;795
10.7.4;51.4 Mechanisms of kidney injury and capacity for repair;797
10.7.5;51.5 Kidney injury and repair in balance with fibrosis;797
10.7.6;51.6 Mesenchymal stromal cells as delivery tools for therapies;798
10.7.7;51.7 Clinical trials with mesenchymal stromal cells;799
10.7.8;51.8 The antifibrotic functions of relaxin;801
10.7.9;51.9 Combination therapy using mesenchymal stromal cells and relaxin;802
10.7.10;51.10 Conclusions;802
10.7.11;References;803
10.8;Chapter 52: The biology and potential clinical applications of mesenchymal stromal cells in diseases of the lung;808
10.8.1;52.1 Introduction to lung disease;808
10.8.1.1;52.1.1 The global burden of lung disease;808
10.8.1.2;52.1.2 The pathogenesis of lung diseases;808
10.8.1.3;52.1.3 The range of lung diseases;809
10.8.2;52.2 What are stem cells?;809
10.8.3;52.3 What are mesenchymal stromal cells?;809
10.8.4;52.4 Lung-resident mesenchymal stromal cells;810
10.8.5;52.5 Tracking mesenchymal stromal cells in the body;810
10.8.6;52.6 The properties of mesenchymal stromal cells that favor repair;810
10.8.6.1;52.6.1 Avoidance of immune recognition;810
10.8.6.2;52.6.2 Mechanisms of mesenchymal-stromal-cell-mediated immunomodulation;810
10.8.6.3;52.6.3 Mesenchymal-stromal-cell-mediated repair via trophic factors;813
10.8.7;52.7 Mesenchymal stromal cells as delivery agents for drugs;813
10.8.7.1;52.7.1 Viral transduction;813
10.8.7.2;52.7.2 Genetic modulation;814
10.8.7.3;52.7.3 Nanoparticle incorporation;814
10.8.7.4;52.7.4 Surface modification;814
10.8.7.5;52.7.5 Preconditioned mesenchymal stromal cells;814
10.8.8;52.8 Preclinical and clinical studies of mesenchymal stromal cells in pulmonary diseases;814
10.8.8.1;52.8.1 Idiopathic pulmonary fibrosis;814
10.8.8.2;52.8.2 Chronic obstructive pulmonary disease;817
10.8.8.3;52.8.3 Acute lung injury and acute respiratory distress syndrome;818
10.8.9;52.9 Challenges in mesenchymal stromal cell administration in lung diseases;819
10.8.9.1;52.9.1 Optimal dosage of mesenchymal stromal cells;819
10.8.9.2;52.9.2 Timing of mesenchymal stromal cell administration;820
10.8.10;52.10 Summary and conclusions;820
10.8.11;References;820
10.9;Chapter 53: The role of mesenchymal stromal cells in diseases of the lung;825
10.9.1;53.1 Introduction;825
10.9.2;53.2 Pulmonary fibrosis;825
10.9.2.1;53.2.1 Animal models;826
10.9.2.2;53.2.2 Clinical trials of mesenchymal stromal cells;826
10.9.3;53.3 Asthma;826
10.9.3.1;53.3.1 Preclinical models;828
10.9.3.2;53.3.2 Clinical trials of mesenchymal stromal cells;828
10.9.4;53.4 Obliterative bronchiolitis;828
10.9.4.1;53.4.1 Preclinical animal models;828
10.9.4.2;53.4.2 Clinical trials of mesenchymal stromal cells;829
10.9.5;53.5 Chronic obstructive pulmonary disease and emphysema;829
10.9.5.1;53.5.1 Preclinical animal models;830
10.9.5.2;53.5.2 Clinical trials with mesenchymal stromal cells;830
10.9.6;53.6 Bronchopulmonary dysplasia;830
10.9.6.1;53.6.1 Preclinical animal models;830
10.9.6.2;53.6.2 Clinical trials using mesenchymal stromal cells;830
10.9.7;53.7 Acute respiratory distress syndrome and acute lung injury;830
10.9.7.1;53.7.1 Preclinical animal models;831
10.9.7.2;53.7.2 Clinical trials with mesenchymal stromal cells;831
10.9.8;53.8 Conclusions;831
10.9.9;References;831
10.10;Chapter 54: Mesenchymal stromal cells for the treatment of autoimmune diseases;832
10.10.1;54.1 Cell biology of endogenous mesenchymal stromal cells;832
10.10.1.1;54.1.1 Mesenchymal stromal cells coordinate hematopoietic stem cell development;833
10.10.1.2;54.1.2 Mesenchymal stromal cells and central tolerance in the bone marrow;833
10.10.2;54.2 Cell biology of mesenchymal stromal cells in culture;834
10.10.2.1;54.2.1 Mesenchymal stromal cells and B cell immunosuppression;835
10.10.2.2;54.2.2 Mesenchymal stromal cell and T cell co-culture assays;835
10.10.3;54.3 Immunosuppression: lessons from oncology;835
10.10.3.1;54.3.1 Programmed death ligand 1 and immunosuppression by tumors;836
10.10.3.2;54.3.2 Programmed death ligand 1 and immunosuppression by mesenchymal stromal cells;836
10.10.3.3;54.3.3 Indoleamine 2,3-dioxygenase and immunosuppression by tumors;837
10.10.3.4;54.3.4 Indoleamine 2,3-dioxygenase and immunosuppression by mesenchymal stromal cells;837
10.10.4;54.4 Mesenchymal stromal cell response to inflammatory signals: licensing and integration;838
10.10.4.1;54.4.1 Mesenchymal stromal cells and complement;838
10.10.4.2;54.4.2 Mesenchymal stromal cells and toll-like receptors;839
10.10.4.3;54.4.3 Interferon-? in the immune response;840
10.10.4.4;54.4.4 Mesenchymal stromal cells and interferon-?;841
10.10.4.5;54.4.5 Tumor necrosis factor-? in the immune response;841
10.10.4.6;54.4.6 Synergy of interferon-? and tumor necrosis factor-? in mesenchymal stromal cells;842
10.10.5;54.5 Strength of signal and integration;842
10.10.6;54.6 Clinical applications of mesenchymal stromal cells for immune-mediated diseases;844
10.10.6.1;54.6.1 How in vitro data inform assessment of clinical efficacy;844
10.10.6.2;54.6.2 Random donor, industrial scale;844
10.10.6.3;54.6.3 Allogeneic mesenchymal stromal cells, low passage;845
10.10.6.4;54.6.4 Autologous mesenchymal stromal cells for autoimmune diseases;846
10.10.7;54.7 Conclusions and next steps;847
10.10.8;References;847
10.11;Chapter 55: The role of mesenchymal stromal cells in bacterial infection;852
10.11.1;55.1 Introduction;852
10.11.2;55.2 Experimental models of bacterial infection and sepsis;853
10.11.3;55.3 Effects of mesenchymal stromal cells on the innate immune response;854
10.11.4;55.4 Effects of mesenchymal stromal cells on the adaptive immune response;857
10.11.5;55.5 Antimicrobial activity of mesenchymal stromal cells;857
10.11.6;55.6 Mesenchymal stromal cells and endothelial/epithelial dysfunction;857
10.11.7;55.7 Mesenchymal stromal cells and effect on organ injury in infection;857
10.11.8;55.8 Mesenchymal stromal cell cytokine and growth factor production;858
10.11.9;55.9 Toll-like receptors and mesenchymal stromal cells;859
10.11.10;55.10 Mesenchymal stromal cell homing;859
10.11.11;55.11 Mesenchymal stromal cell response to oxidative stress;859
10.11.12;55.12 Paracrine effects of mesenchymal stromal cells;859
10.11.13;55.13 Transcriptomic analysis of mesenchymal stromal cell therapy in sepsis;860
10.11.14;55.14 Summary;860
10.11.15;References;860
10.12;Chapter 56: The use of mesenchymal stromal cells in solid organ transplantation;863
10.12.1;56.1 Introduction;863
10.12.2;56.2 Potential effects of mesenchymal stromal cells in solid organ transplantation;863
10.12.3;56.3 Immunomodulation;864
10.12.4;56.4 Tissue and organ regeneration;864
10.12.5;56.5 Prevention of ischemia-reperfusion injury;864
10.12.6;56.6 Mesenchymal stromal cell administration in solid organ transplantation;864
10.12.6.1;56.6.1 Kidney transplantation;864
10.12.6.2;56.6.2 Liver transplantation;867
10.12.6.3;56.6.3 Heart transplantation;869
10.12.6.4;56.6.4 Lung transplantation;869
10.12.6.5;56.6.5 Pancreas and islet transplantation;869
10.12.6.6;56.6.6 Bowel transplantation;870
10.12.7;56.7 Conclusions;870
10.12.8;References;870
10.13;Chapter 57: The role of mesenchymal stromal cells in allogeneic hematopoietic stem cell transplantation;874
10.13.1;57.1 The immunobiology of allogeneic hematopoietic stem cell transplantation;874
10.13.1.1;57.1.1 Graft rejection and late marrow failure;874
10.13.1.2;57.1.2 Graft-versus-host disease;874
10.13.1.3;57.1.3 The graft-versus-leukemia effect;875
10.13.1.4;57.1.4 The recipient's response to infection;875
10.13.2;57.2 The immunobiology of mesenchymal stromal cells;875
10.13.3;57.3 The role of mesenchymal stromal cells in the expansion of hematopoietic stem cells;875
10.13.4;57.4 The role of mesenchymal stromal cells in marrow graft rejection;875
10.13.5;57.5 The role of mesenchymal stromal cells in the prevention of acute graft-versus-host disease;876
10.13.6;57.6 The role of mesenchymal cells in the treatment of corticosteroid-refractory acute graft-versus-host disease;876
10.13.7;57.7 The mesenchymal stromal cell exosome: a substitute for the mesenchymal stromal cell?;877
10.13.8;References;877
10.14;Chapter 58: The role of mesenchymal stromal cells in the management of skin wounds;879
10.14.1;58.1 Introduction;879
10.14.2;58.2 The wound healing process;879
10.14.3;58.3 The role of mesenchymal stromal cells in the wound healing process;880
10.14.3.1;58.3.1 Immune modulation;880
10.14.3.2;58.3.2 Antimicrobial activity;880
10.14.3.3;58.3.3 Chemotactic and migratory activities;880
10.14.3.4;58.3.4 Paracrine activity;880
10.14.3.5;58.3.5 Differentiation;880
10.14.4;58.4 Conclusions and the future;880
10.14.5;References;881
10.15;Chapter 59: The role of mesenchymal stromal cells in skin wound healing;883
10.15.1;59.1 Summary;883
10.15.2;59.2 Introduction;883
10.15.3;59.3 The role of bone-marrow-derived mesenchymal stromal cells in wound healing;883
10.15.4;59.4 The role of adipose-tissue-derived mesenchymal stromal cells in wound healing;887
10.15.5;59.5 The role of mesenchymal stromal cells from placental tissues in wound healing;889
10.15.6;59.6 The role of mesenchymal stromal cells from dermal tissue in wound healing;890
10.15.7;59.7 The role of mesenchymal stromal cells from blood in wound healing;891
10.15.8;59.8 Questions and challenges regarding mesenchymal stromal cell administration in wound healing;891
10.15.9;59.9 Conclusions;891
10.15.10;References;891
11;Section VII: Mesenchymal stromal cells as delivery vehicles for therapeutic agents;895
11.1;Chapter 60: The role of mesenchymal stromal cells in human brain tumors;897
11.1.1;60.1 Introduction;897
11.1.2;60.2 Mesenchymal stromal cells in the therapy of human gliomas;898
11.1.3;60.3 Cellular therapy for gliomas;898
11.1.4;60.4 The advantages of mesenchymal stromal cells in clinical use;899
11.1.5;60.5 The rationale for using mesenchymal stromal cells in glioma therapy;899
11.1.6;60.6 Mechanisms underlying mesenchymal stromal cell tropism for gliomas;901
11.1.7;60.7 Strategies to enhance mesenchymal stromal cell homing to gliomas;902
11.1.8;60.8 Types of therapeutic cargo;902
11.1.8.1;60.8.1 Secreted proteins;902
11.1.8.2;60.8.2 Prodrug enzymes;903
11.1.8.3;60.8.3 Replication-competent oncolytic viruses;903
11.1.8.4;60.8.4 Antibodies;904
11.1.8.5;60.8.5 Nanoparticles;904
11.1.9;60.9 Delivery routes of mesenchymal stromal cells in clinical applications;904
11.1.10;60.10 Mesenchymal stem cells in the biology of gliomas;905
11.1.11;60.11 Controversy over tumor-associated mesenchymal stromal cells in solid tumors and gliomas;905
11.1.12;60.12 A model of mesenchymal stromal cells in glioma biology;906
11.1.13;60.13 Prospects for clinical use of bone-marrow-derived mesenchymal stromal cells in glioma therapy;906
11.1.14;References;907
11.2;Chapter 61: Mesenchymal stromal cells as gene delivery vehicles to treat nonmalignant diseases;911
11.2.1;61.1 Introduction;911
11.2.2;61.2 What are mesenchymal stromal cells?;911
11.2.3;61.3 Genetic modification of mesenchymal stromal cells;912
11.2.3.1;61.3.1 Safety concerns;912
11.2.3.2;61.3.2 Choice of vector system;912
11.2.4;61.4 Preclinical models of gene-modified mesenchymal stromal cells: mesenchymal stromal cell migration and survival;913
11.2.5;61.5 Gene-modified mesenchymal stromal cells as immune modulators;915
11.2.6;61.6 Gene-modified mesenchymal stromal cells in skeletal disorders;916
11.2.7;61.7 Gene-modified mesenchymal stromal cells in cardiovascular disease;918
11.2.8;61.8 Gene-modified mesenchymal stromal cells in kidney disease;919
11.2.9;61.9 Gene-modified mesenchymal stromal cells in neurological disease;919
11.2.10;61.10 Gene-modified mesenchymal stromal cells in other nonmalignant diseases;921
11.2.10.1;61.10.1 Hemophilia;921
11.2.10.2;61.10.2 Metachromatic leukodystrophy;921
11.2.10.3;61.10.3 Mucopolysaccharidosis type VII;921
11.2.10.4;61.10.4 Diabetes mellitus;921
11.2.11;61.11 Conclusions and future directions;921
11.2.12;References;923
11.3;Chapter 62: Gene therapy for cancer using mesenchymal stromal cells;930
11.3.1;62.1 Introduction;930
11.3.1.1;62.1.1 Biological characteristics of mesenchymal stromal cells;930
11.3.1.2;62.1.2 Immunomodulatory effects of mesenchymal stromal cells on immune cells;931
11.3.1.3;62.1.3 Tumor homing of mesenchymal stromal cells;931
11.3.2;62.2 Applications of genetically engineered mesenchymal stromal cells for cancer therapy;931
11.3.2.1;62.2.1 Interferons;931
11.3.2.2;62.2.2 Interleukins;932
11.3.2.3;62.2.3 Chemokines;932
11.3.2.4;62.2.4 Suicide genes;932
11.3.2.5;62.2.5 Other approaches;932
11.3.3;62.3 Molecular mechanisms of mesenchymal stromal cell accumulation at tumor sites;932
11.3.3.1;62.3.1 Migratory factors;933
11.3.3.2;62.3.2 Interactions between mesenchymal stromal cells and endothelial cells;933
11.3.4;62.4 Considerations in the use of genetically engineered mesenchymal stromal cells in cancer therapy;933
11.3.5;62.5 Summary and conclusions;934
11.3.6;References;934
12;Section VIII: The present and the future;937
12.1;Chapter 63: Breaking news;939
12.1.1;63.1 In vitro laboratory studies;939
12.1.2;63.2 Preclinical in vivo animal studies;941
12.1.3;63.3 Clinical trials;946
12.1.4;63.4 Regulatory approval for marketing mesenchymal stromal cell products;947
12.1.5;References;947
12.2;Chapter 64: Reconciling the stem cell and paracrine paradigms of mesenchymal stem cell function;950
12.2.1;64.1 Summary;950
12.2.2;64.2 Introduction;950
12.2.3;64.3 The stem cell paradigm revisited;951
12.2.4;64.4 The paracrine paradigm;952
12.2.4.1;64.4.1 "Mesenchymal stem cell pharmacology": cells are not drug-like;953
12.2.4.2;64.4.2 Priming to enhance mesenchymal stem cell paracrine action also impacts cell growth and survival;954
12.2.4.3;64.4.3 Licensing of immunomodulatory activity biases cell differentiation;954
12.2.5;64.5 Modeling mesenchymal stem cell function using lessons learned from immunology;954
12.2.6;64.6 A stem-cell-centric view of mesenchymal stem cells;957
12.2.7;64.7 Closing remarks;958
12.2.8;References;958
13;Glossary;965
13.1;Historical notes;985
14;Index;987
15;End User License Agreement;1007mehr