Stem Cell-Dependent Therapies (eBook)

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Gerhard Gross, Helmholtz Centre for Infection Research, Braunschweig, Germany; Thomas Häupl, Charité, Berlin, Germany.

Preface 5
Contributing authors 7
1 Mesenchymal stem cells in the context of stem cell biology 19
1.1 Introduction – Definitions 19
1.2 Embryonic and adult tissue stem cells 20
1.3 Adult tissue stem cells and progenitors 21
1.4 Adult stem cells and tissue homeostasis 23
1.5 Adult stem cell niches 23
1.6 Commitment and differentiation 25
1.7 The case for bone marrow MSCs 26
1.8 Clinical prospects 28
1.9 Concluding remark 29
References 29
2 Are mesenchymal stem cells immune privileged? 35
2.1 Introduction – Definition of mesenchymal stem cells (MSCs) 35
2.2 The immunosuppressive effect of MSCs on immune cells 36
2.3 The potential clinical benefits of MSCs as immunosuppressants 38
2.4 The mechanisms of immunosuppression by MSCs 39
2.5 The mechanisms of immunosuppression by human MSCs 39
2.6 Immunosuppression by murine MSCs and the species difference underlying the mechanisms of immunosuppression by MSCs 43
2.7 Immunosuppression mediated by fibroblasts 46
2.8 The mechanisms of the immunosuppressive effect of MSCs are shared with other nonstromal cells 46
2.9 How long can MSCs survive in vivo? 46
2.10 Conclusion and discussion 47
References 49
3 Mesenchymal stem cell therapies for autoimmune diseases 55
3.1 Introduction 55
3.2 Autoimmune disease 57
3.3 Mesenchymal stem cells (MSCs) 59
3.3.1 Animal models 60
3.4 Results of MSCs clinical trials 62
3.5 Safety of MSCs 63
3.6 Conclusion 63
References 64
4 Mesenchymal stem cells in osteoarthritis and rheumatic disease 69
4.1 Introduction – Rheumatic diseases 69
4.2 Rheumatoid arthritis (RA) 69
4.3 Osteoarthritis (OA) 71
4.4 MSCs in healthy and rheumatic joint tissues 73
4.5 Application of MSCs in rheumatic diseases 74
4.6 MSCs application in animals 78
4.7 Clinical studies in humans 84
4.8 Risks and benefits of MSCs treatments in rheumatic diseases 86
References 88
5 Mesenchymal stem cells in enthesis formation and repair 101
5.1 Introduction 101
5.2 Structure of the tendon-to-bone junction 102
5.3 Enthesis resident T cells are involved in enthesopathies provoking inflammation and bone remodeling 103
5.4 Biomaterials and growth factor-dependent regeneration of tendon-to-bone junctions 105
5.5 Biomechanical stimulation for enthesis repair 106
5.6 Mesenchymal stem cells (MSCs) 106
5.7 Stem cell-dependent approaches for repair of osteotendinous junctions 107
5.8 Stem cell-dependent delivery of growth factors 109
5.9 Stem cell-dependent delivery of tenogenic transcription factors 111
5.10 Stem cell-dependent delivery of matrix metalloproteinases 112
5.11 Trophic activities of MSCs in enthesis repair 112
5.12 Outlook 113
Acknowledgment 114
References 114
6 Mesenchymal stem cells for clinical/therapeutic interventions of graft-versus-host disease 119
6.1 Clinical graft-versus-host disease 119
6.2 Chronic graft-versus-host disease 120
6.3 Rationale to use mesenchymal stromal cells for treatment of GvHD 121
6.4 Experience of MSCs in clinical acute graft-versus-host disease 123
6.5 Treatment of acute GvHD with stromal cells from alternate sources, adipose tissue-derived, umbilical cord blood-derived or fetal membrane-derived stromal cells 128
6.6 Mesenchymal stromal cells for treatment of chronic graft-versus-host disease 129
6.7 Clinical trials of prophylaxis with mesenchymal stromal cells for graft-versus-host disease 131
6.8 Discussion on clinical use of mesenchymal stem cells 133
6.9 How should we best utilize MSC treatment of GvHD? 134
References 137
7 Mesenchymal stem cells for graft-versus-host disease in experimental animal models 143
7.1 Introduction – Experimental models of graft-versus-host disease (GvHD) 143
7.2 Immunobiology of experimental GvHD 145
7.3 Mesenchymal stromal cells in mice 146
7.4 Mesenchymal stromal cells and mouse models of graft-versus-host disease 148
References 154
8 Mesenchymal stem cells and organ transplantation: initial clinical results 161
8.1 Introduction 161
8.2 Rationale for the use of MSCs in organ transplantation 162
8.2.1 Shortage of donor organs for transplantation 162
8.2.2 Ischemia-reperfusion injury 163
8.2.3 Chronic immunosuppression 163
8.3 Considerations regarding the choice of the clinical protocols 164
8.3.1 Definition, identity and product release criteria for human MSCs preparations 165
8.3.2 Source of human MSCs 165
8.3.3 Potential interactions between MSCs and concomitant therapy 167
8.3.4 Safety of MSCs-based treatments 168
8.4 Clinical MSCs and solid organ transplantation trials 169
8.4.1 Autologous MSCs in the induction phase with standard immunosuppression 169
8.4.2 Autologous MSCs in the induction phase with avoidance of biologics at induction and reduced maintenance immunosuppression 172
8.4.3 Allogeneic MSCs in the induction phase 173
8.4.4 Autologous MSCs for the treatment of biopsy-proven subclinical rejection, progressive renal interstitial fibrosis and tubular atrophy 174
8.5 Future perspectives 176
Acknowledgments: 176
References 177
9 Stem cell therapy in patients with ischemic heart disease 181
9.1 Introduction 181
9.2 Cell type and source for clinical therapy 183
9.3 Mechanisms behind regeneration of damaged myocardium 184
9.4 Preclinical experience with stem cells for IHD 187
9.5 Cell-based therapy in patients with IHD 187
9.6 MSCs in patients with IHD 189
9.7 Ongoing clinical trials using MSCs 192
9.8 Cell delivery and engraftment 192
9.9 Perspectives 196
9.10 Conclusion 197
References 197
10 Mesenchymal stem cells as a strategy for the treatment of multiple sclerosis and other diseases of the central nervous system 203
10.1 Introduction 203
10.2 MSCs transplantation for neurological diseases: why, which, and how 204
10.3 Vascular diseases: ischemic stroke 205
10.3.1 Preclinical studies 205
10.3.2 Clinical studies 207
10.4 Trauma spinal cord injury 208
10.4.1 Preclinical studies 209
10.4.2 Clinical studies 210
10.5 Extrapyramidal diseases 210
10.5.1 Parkinson’s disease (PD) 210
10.5.2 Preclinical studies 211
10.5.3 Clinical studies 212
10.5.4 Huntington’s disease (HD) 212
10.5.5 Preclinical studies 213
10.6 Multiple system atrophy (MSA) 214
10.6.1 Preclinical studies 214
10.6.2 Clinical studies 215
10.7 CNS demyelinating diseases: multiple sclerosis 215
10.7.1 Preclinical studies 216
10.7.2 Clinical studies 217
10.8 Motor neuron diseases: amyotrophic lateral sclerosis (ALS) 218
10.8.1 Preclinical studies 218
10.8.2 Clinical studies 219
10.9 Dementia: Alzheimer’s disease (AD) 220
10.9.1 Preclinical studies 220
10.9.2 Clinical studies 221
10.10 Concluding remarks 221
References 222
11 Mesenchymal stem cells for the treatment of inflammatory bowel disease 229
11.1 Introduction 229
11.2 Immunology and intestinal barrier function 230
11.3 Cell-based treatments for IBD 233
11.3.1 Hematopoietic cell transplantation 233
11.4 T regulatory cells (Tregs) 234
11.5 Mesenchymal stem cells (MSCs) 235
11.5.1 Immunologic basis for MSCs and IBD 235
11.6 MSC homing and engraftment 237
11.7 MSC clinical trials 240
11.8 Summary and future directions 242
References 244
12 Mesenchymal stem cells in chronic lung diseases: COPD and lung fibrosis 251
12.1 Introduction 251
12.2 Idiopathic pulmonary fibrosis 253
12.3 MSCs and animal models of fibrotic lung disorders 256
12.4 Chronic obstructive pulmonary disease (COPD) 264
12.5 Conclusions and future directions 270
Acknowledgments 271
References 271
13 Mesenchymal stem cells as therapeutics for liver repair and regeneration 281
13.1 Introduction 281
13.2 Cell therapy for liver disease 282
13.3 The ideal cell for liver regeneration 283
13.4 Mesenchymal stem cells (MSCs) as cellular therapeutics 284
13.5 MSCs for treating liver disease 287
13.5.1 In vitro models to study MSCs hepatic differentiation 287
13.5.2 In vivo models to study MSCs as cellular therapies for liver disease/injury 288
13.6 The fetal sheep model 291
13.7 Clinical trials using MSCs for liver regeneration 297
13.8 Summary/Conclusions: 298
References 299
14 Mesenchymal stem cells attenuate renal fibrosis 311
14.1 Introduction – Kidney function 311
14.2 Kidney dysfunction and chronic kidney disease (CDK) 313
14.2.1 Molecular and cellular interaction in renal fibrosis 314
14.3 Mesenchymal stem cells (MSCs): Definition and basic features 316
14.3.1 Therapeutic potential of MSCs and their mechanisms of action in the repair/regeneration of tissue injury 316
14.4 MSCs and kidney diseases 319
14.4.1 MSCs have a prominent antifibrotic effect in distinct models of experimental chronic kidney diseases 319
14.4.2 Mechanisms related to MSCs prevent renal fibrosis 321
14.5 Final considerations 322
References 323
15 Immunomodulation by mesenchymal stem cells – a potential therapeutic strategy for type 1 diabetes 327
15.1 Introduction 327
15.2 Mechanisms of immunomodulation 328
15.3 MSC therapy for type 1 diabetes (T1D) 329
15.3.1 Why does MSC therapy hold value in T1D? 329
15.3.2 Preclinical studies to prevent and reverse T1D 330
15.3.3 MSC implications in islet cell transplantation 331
15.3.4 MSCs and clinical trials for T1D 332
15.4 Safety of MSC therapy 333
References: 333
16 Fibrogenic potential of human multipotent mesenchymal stem cells in inflammatory environments 337
16.1 Introduction 337
16.2 Fibrogenic potential in ex vivo expanded MSCs 338
16.3 Evidence of MSCs infiltration into tumor stroma 339
16.4 Controversies regarding therapeutic benefits of bone marrow-derived MSCs in liver fibrosis 340
16.5 Limited contribution of MSCs to liver regeneration in acute liver injury 342
16.6 Conclusion 344
References 344
17 Mesenchymal stem cells and the tumor microenvironment 349
17.1 Introduction 349
17.2 The tumor microenvironment and its role in cancer initiation and progression 351
17.3 How do we define MSCs in cancer? 352
17.4 What are the roles of MSCs in cancer progression? 353
17.4.1 Effect of MSCs on tumor cell proliferation 355
17.4.2 MSCs promote survival 355
17.4.3 MSCs are proangiogenic 356
17.4.4 MSCs have an immunosuppressive function 356
17.4.5 MSCs promote epithelial to mesenchymal transition 357
17.5 How do tumor cells communicate with MSCs? 359
17.6 Are MSCs recruited by tumor cells? 361
17.7 Can we target MSCs in human cancer? 363
17.8 Conclusion 364
References 364
18 Mesenchymal stem cells as a carrier for tumor-targeting therapeutics 371
18.1 Introduction 371
18.2 Enhanced angiogenesis as a target for tumor therapy 372
18.3 Why current therapies are not effective enough 373
18.3.1 Shortcomings of current anti-angiogenic pharmaceuticals 374
18.4 Why mesenchymal stem cells would be useful for tumor targeting 376
18.4.1 The tumor-homing properties of MSCs 376
18.4.2 MSCs as a diagnostic tool 379
18.4.3 Antitumor effects of unmanipulated MSCs 379
18.4.4 Vesicular communication of MSCs: How MSCs can be used as a drug-delivery vehicle 380
18.5 MSCs as a gene product-delivering vehicle 382
18.5.1 Genetically modified MSCs for therapeutic delivery 382
18.5.2 Potential for MSCs-delivered anti-angiogenic therapies 383
18.5.3 MSCs-mediated tumor-homing of oncolytic adenovirus enhances tumor therapy 384
18.5.4 Delivery of TRAIL by genetically modified MSCs to induce apoptosis 385
18.5.5 Tumor-specific promoter-driving thymidine kinase (TK) expression for prodrug conversion 385
18.6 Methods of therapeutic MSCs administration 387
18.7 The advantage of MSCs being immunoprivileged 388
18.8 Sources of acquiring MSCs for tumor therapy 389
18.9 Remaining challenges for the use of MSCs to deliver therapeutics 390
18.9.1 The immunoprivileged nature of MSCs 390
18.9.2 Varying responses to MSCs depending on cancer type, injection site, etc. 390
18.9.3 Changes in MSCs induced by cancer cells within the tumor microenvironment 391
18.10 Summary and prospective 393
Acknowledgments 393
References 394
19 Systems biology approach to stem cells, tissues and inflammation 399
19.1 Introduction 399
19.2 Biological aspects 400
19.2.1 Cells are the regulatory units 400
19.2.2 Influence of cell number and phenotype 401
19.3 Technological aspects 401
19.3.1 Technology and type of molecules 401
19.3.2 When “pictures start moving” 402
19.4 Mathematical aspects 403
19.4.1 Comparative statistics and interpretation 403
19.4.2 Interpretation based on pre-existing knowledge 404
19.4.3 Network models 404
19.5 Systems biology of differentiation 406
19.6 Important tasks 407
19.7 Conclusion 408
References 409
Index 413