Stem Cell-Dependent Therapies

1 - Preface [Seite 5]
2 - Contributing authors [Seite 7]
3 - 1 Mesenchymal stem cells in the context of stem cell biology [Seite 19]
3.1 - 1.1 Introduction - Definitions [Seite 19]
3.2 - 1.2 Embryonic and adult tissue stem cells [Seite 20]
3.3 - 1.3 Adult tissue stem cells and progenitors [Seite 21]
3.4 - 1.4 Adult stem cells and tissue homeostasis [Seite 23]
3.5 - 1.5 Adult stem cell niches [Seite 23]
3.6 - 1.6 Commitment and differentiation [Seite 25]
3.7 - 1.7 The case for bone marrow MSCs [Seite 26]
3.8 - 1.8 Clinical prospects [Seite 28]
3.9 - 1.9 Concluding remark [Seite 29]
3.10 - References [Seite 29]
4 - 2 Are mesenchymal stem cells immune privileged? [Seite 35]
4.1 - 2.1 Introduction - Definition of mesenchymal stem cells (MSCs) [Seite 35]
4.2 - 2.2 The immunosuppressive effect of MSCs on immune cells [Seite 36]
4.3 - 2.3 The potential clinical benefits of MSCs as immunosuppressants [Seite 38]
4.4 - 2.4 The mechanisms of immunosuppression by MSCs [Seite 39]
4.5 - 2.5 The mechanisms of immunosuppression by human MSCs [Seite 39]
4.6 - 2.6 Immunosuppression by murine MSCs and the species difference underlying the mechanisms of immunosuppression by MSCs [Seite 43]
4.7 - 2.7 Immunosuppression mediated by fibroblasts [Seite 46]
4.8 - 2.8 The mechanisms of the immunosuppressive effect of MSCs are shared with other nonstromal cells [Seite 46]
4.9 - 2.9 How long can MSCs survive in vivo? [Seite 46]
4.10 - 2.10 Conclusion and discussion [Seite 47]
4.11 - References [Seite 49]
5 - 3 Mesenchymal stem cell therapies for autoimmune diseases [Seite 55]
5.1 - 3.1 Introduction [Seite 55]
5.2 - 3.2 Autoimmune disease [Seite 57]
5.3 - 3.3 Mesenchymal stem cells (MSCs) [Seite 59]
5.3.1 - 3.3.1 Animal models [Seite 60]
5.4 - 3.4 Results of MSCs clinical trials [Seite 62]
5.5 - 3.5 Safety of MSCs [Seite 63]
5.6 - 3.6 Conclusion [Seite 63]
5.7 - References [Seite 64]
6 - 4 Mesenchymal stem cells in osteoarthritis and rheumatic disease [Seite 69]
6.1 - 4.1 Introduction - Rheumatic diseases [Seite 69]
6.2 - 4.2 Rheumatoid arthritis (RA) [Seite 69]
6.3 - 4.3 Osteoarthritis (OA) [Seite 71]
6.4 - 4.4 MSCs in healthy and rheumatic joint tissues [Seite 73]
6.5 - 4.5 Application of MSCs in rheumatic diseases [Seite 74]
6.6 - 4.6 MSCs application in animals [Seite 78]
6.7 - 4.7 Clinical studies in humans [Seite 84]
6.8 - 4.8 Risks and benefits of MSCs treatments in rheumatic diseases [Seite 86]
6.9 - References [Seite 88]
7 - 5 Mesenchymal stem cells in enthesis formation and repair [Seite 101]
7.1 - 5.1 Introduction [Seite 101]
7.2 - 5.2 Structure of the tendon-to-bone junction [Seite 102]
7.3 - 5.3 Enthesis resident T cells are involved in enthesopathies provoking inflammation and bone remodeling [Seite 103]
7.4 - 5.4 Biomaterials and growth factor-dependent regeneration of tendon-to-bone junctions [Seite 105]
7.5 - 5.5 Biomechanical stimulation for enthesis repair [Seite 106]
7.6 - 5.6 Mesenchymal stem cells (MSCs) [Seite 106]
7.7 - 5.7 Stem cell-dependent approaches for repair of osteotendinous junctions [Seite 107]
7.8 - 5.8 Stem cell-dependent delivery of growth factors [Seite 109]
7.9 - 5.9 Stem cell-dependent delivery of tenogenic transcription factors [Seite 111]
7.10 - 5.10 Stem cell-dependent delivery of matrix metalloproteinases [Seite 112]
7.11 - 5.11 Trophic activities of MSCs in enthesis repair [Seite 112]
7.12 - 5.12 Outlook [Seite 113]
7.13 - Acknowledgment [Seite 114]
7.14 - References [Seite 114]
8 - 6 Mesenchymal stem cells for clinical/therapeutic interventions of graft-versus-host disease [Seite 119]
8.1 - 6.1 Clinical graft-versus-host disease [Seite 119]
8.2 - 6.2 Chronic graft-versus-host disease [Seite 120]
8.3 - 6.3 Rationale to use mesenchymal stromal cells for treatment of GvHD [Seite 121]
8.4 - 6.4 Experience of MSCs in clinical acute graft-versus-host disease [Seite 123]
8.5 - 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 [Seite 128]
8.6 - 6.6 Mesenchymal stromal cells for treatment of chronic graft-versus-host disease [Seite 129]
8.7 - 6.7 Clinical trials of prophylaxis with mesenchymal stromal cells for graft-versus-host disease [Seite 131]
8.8 - 6.8 Discussion on clinical use of mesenchymal stem cells [Seite 133]
8.9 - 6.9 How should we best utilize MSC treatment of GvHD? [Seite 134]
8.10 - References [Seite 137]
9 - 7 Mesenchymal stem cells for graft-versus-host disease in experimental animal models [Seite 143]
9.1 - 7.1 Introduction - Experimental models of graft-versus-host disease (GvHD) [Seite 143]
9.2 - 7.2 Immunobiology of experimental GvHD [Seite 145]
9.3 - 7.3 Mesenchymal stromal cells in mice [Seite 146]
9.4 - 7.4 Mesenchymal stromal cells and mouse models of graft-versus-host disease [Seite 148]
9.5 - References [Seite 154]
10 - 8 Mesenchymal stem cells and organ transplantation: initial clinical results [Seite 161]
10.1 - 8.1 Introduction [Seite 161]
10.2 - 8.2 Rationale for the use of MSCs in organ transplantation [Seite 162]
10.2.1 - 8.2.1 Shortage of donor organs for transplantation [Seite 162]
10.2.2 - 8.2.2 Ischemia-reperfusion injury [Seite 163]
10.2.3 - 8.2.3 Chronic immunosuppression [Seite 163]
10.3 - 8.3 Considerations regarding the choice of the clinical protocols [Seite 164]
10.3.1 - 8.3.1 Definition, identity and product release criteria for human MSCs preparations [Seite 165]
10.3.2 - 8.3.2 Source of human MSCs [Seite 165]
10.3.3 - 8.3.3 Potential interactions between MSCs and concomitant therapy [Seite 167]
10.3.4 - 8.3.4 Safety of MSCs-based treatments [Seite 168]
10.4 - 8.4 Clinical MSCs and solid organ transplantation trials [Seite 169]
10.4.1 - 8.4.1 Autologous MSCs in the induction phase with standard immunosuppression [Seite 169]
10.4.2 - 8.4.2 Autologous MSCs in the induction phase with avoidance of biologics at induction and reduced maintenance immunosuppression [Seite 172]
10.4.3 - 8.4.3 Allogeneic MSCs in the induction phase [Seite 173]
10.4.4 - 8.4.4 Autologous MSCs for the treatment of biopsy-proven subclinical rejection, progressive renal interstitial fibrosis and tubular atrophy [Seite 174]
10.5 - 8.5 Future perspectives [Seite 176]
10.6 - Acknowledgments: [Seite 176]
10.7 - References [Seite 177]
11 - 9 Stem cell therapy in patients with ischemic heart disease [Seite 181]
11.1 - 9.1 Introduction [Seite 181]
11.2 - 9.2 Cell type and source for clinical therapy [Seite 183]
11.3 - 9.3 Mechanisms behind regeneration of damaged myocardium [Seite 184]
11.4 - 9.4 Preclinical experience with stem cells for IHD [Seite 187]
11.5 - 9.5 Cell-based therapy in patients with IHD [Seite 187]
11.6 - 9.6 MSCs in patients with IHD [Seite 189]
11.7 - 9.7 Ongoing clinical trials using MSCs [Seite 192]
11.8 - 9.8 Cell delivery and engraftment [Seite 192]
11.9 - 9.9 Perspectives [Seite 196]
11.10 - 9.10 Conclusion [Seite 197]
11.11 - References [Seite 197]
12 - 10 Mesenchymal stem cells as a strategy for the treatment of multiple sclerosis and other diseases of the central nervous system [Seite 203]
12.1 - 10.1 Introduction [Seite 203]
12.2 - 10.2 MSCs transplantation for neurological diseases: why, which, and how [Seite 204]
12.3 - 10.3 Vascular diseases: ischemic stroke [Seite 205]
12.3.1 - 10.3.1 Preclinical studies [Seite 205]
12.3.2 - 10.3.2 Clinical studies [Seite 207]
12.4 - 10.4 Trauma spinal cord injury [Seite 208]
12.4.1 - 10.4.1 Preclinical studies [Seite 209]
12.4.2 - 10.4.2 Clinical studies [Seite 210]
12.5 - 10.5 Extrapyramidal diseases [Seite 210]
12.5.1 - 10.5.1 Parkinson's disease (PD) [Seite 210]
12.5.2 - 10.5.2 Preclinical studies [Seite 211]
12.5.3 - 10.5.3 Clinical studies [Seite 212]
12.5.4 - 10.5.4 Huntington's disease (HD) [Seite 212]
12.5.5 - 10.5.5 Preclinical studies [Seite 213]
12.6 - 10.6 Multiple system atrophy (MSA) [Seite 214]
12.6.1 - 10.6.1 Preclinical studies [Seite 214]
12.6.2 - 10.6.2 Clinical studies [Seite 215]
12.7 - 10.7 CNS demyelinating diseases: multiple sclerosis [Seite 215]
12.7.1 - 10.7.1 Preclinical studies [Seite 216]
12.7.2 - 10.7.2 Clinical studies [Seite 217]
12.8 - 10.8 Motor neuron diseases: amyotrophic lateral sclerosis (ALS) [Seite 218]
12.8.1 - 10.8.1 Preclinical studies [Seite 218]
12.8.2 - 10.8.2 Clinical studies [Seite 219]
12.9 - 10.9 Dementia: Alzheimer's disease (AD) [Seite 220]
12.9.1 - 10.9.1 Preclinical studies [Seite 220]
12.9.2 - 10.9.2 Clinical studies [Seite 221]
12.10 - 10.10 Concluding remarks [Seite 221]
12.11 - References [Seite 222]
13 - 11 Mesenchymal stem cells for the treatment of inflammatory bowel disease [Seite 229]
13.1 - 11.1 Introduction [Seite 229]
13.2 - 11.2 Immunology and intestinal barrier function [Seite 230]
13.3 - 11.3 Cell-based treatments for IBD [Seite 233]
13.3.1 - 11.3.1 Hematopoietic cell transplantation [Seite 233]
13.4 - 11.4 T regulatory cells (Tregs) [Seite 234]
13.5 - 11.5 Mesenchymal stem cells (MSCs) [Seite 235]
13.5.1 - 11.5.1 Immunologic basis for MSCs and IBD [Seite 235]
13.6 - 11.6 MSC homing and engraftment [Seite 237]
13.7 - 11.7 MSC clinical trials [Seite 240]
13.8 - 11.8 Summary and future directions [Seite 242]
13.9 - References [Seite 244]
14 - 12 Mesenchymal stem cells in chronic lung diseases: COPD and lung fibrosis [Seite 251]
14.1 - 12.1 Introduction [Seite 251]
14.2 - 12.2 Idiopathic pulmonary fibrosis [Seite 253]
14.3 - 12.3 MSCs and animal models of fibrotic lung disorders [Seite 256]
14.4 - 12.4 Chronic obstructive pulmonary disease (COPD) [Seite 264]
14.5 - 12.5 Conclusions and future directions [Seite 270]
14.6 - Acknowledgments [Seite 271]
14.7 - References [Seite 271]
15 - 13 Mesenchymal stem cells as therapeutics for liver repair and regeneration [Seite 281]
15.1 - 13.1 Introduction [Seite 281]
15.2 - 13.2 Cell therapy for liver disease [Seite 282]
15.3 - 13.3 The ideal cell for liver regeneration [Seite 283]
15.4 - 13.4 Mesenchymal stem cells (MSCs) as cellular therapeutics [Seite 284]
15.5 - 13.5 MSCs for treating liver disease [Seite 287]
15.5.1 - 13.5.1 In vitro models to study MSCs hepatic differentiation [Seite 287]
15.5.2 - 13.5.2 In vivo models to study MSCs as cellular therapies for liver disease/injury [Seite 288]
15.6 - 13.6 The fetal sheep model [Seite 291]
15.7 - 13.7 Clinical trials using MSCs for liver regeneration [Seite 297]
15.8 - 13.8 Summary/Conclusions: [Seite 298]
15.9 - References [Seite 299]
16 - 14 Mesenchymal stem cells attenuate renal fibrosis [Seite 311]
16.1 - 14.1 Introduction - Kidney function [Seite 311]
16.2 - 14.2 Kidney dysfunction and chronic kidney disease (CDK) [Seite 313]
16.2.1 - 14.2.1 Molecular and cellular interaction in renal fibrosis [Seite 314]
16.3 - 14.3 Mesenchymal stem cells (MSCs): Definition and basic features [Seite 316]
16.3.1 - 14.3.1 Therapeutic potential of MSCs and their mechanisms of action in the repair/regeneration of tissue injury [Seite 316]
16.4 - 14.4 MSCs and kidney diseases [Seite 319]
16.4.1 - 14.4.1 MSCs have a prominent antifibrotic effect in distinct models of experimental chronic kidney diseases [Seite 319]
16.4.2 - 14.4.2 Mechanisms related to MSCs prevent renal fibrosis [Seite 321]
16.5 - 14.5 Final considerations [Seite 322]
16.6 - References [Seite 323]
17 - 15 Immunomodulation by mesenchymal stem cells - a potential therapeutic strategy for type 1 diabetes [Seite 327]
17.1 - 15.1 Introduction [Seite 327]
17.2 - 15.2 Mechanisms of immunomodulation [Seite 328]
17.3 - 15.3 MSC therapy for type 1 diabetes (T1D) [Seite 329]
17.3.1 - 15.3.1 Why does MSC therapy hold value in T1D? [Seite 329]
17.3.2 - 15.3.2 Preclinical studies to prevent and reverse T1D [Seite 330]
17.3.3 - 15.3.3 MSC implications in islet cell transplantation [Seite 331]
17.3.4 - 15.3.4 MSCs and clinical trials for T1D [Seite 332]
17.4 - 15.4 Safety of MSC therapy [Seite 333]
17.5 - References: [Seite 333]
18 - 16 Fibrogenic potential of human multipotent mesenchymal stem cells in inflammatory environments [Seite 337]
18.1 - 16.1 Introduction [Seite 337]
18.2 - 16.2 Fibrogenic potential in ex vivo expanded MSCs [Seite 338]
18.3 - 16.3 Evidence of MSCs infiltration into tumor stroma [Seite 339]
18.4 - 16.4 Controversies regarding therapeutic benefits of bone marrow-derived MSCs in liver fibrosis [Seite 340]
18.5 - 16.5 Limited contribution of MSCs to liver regeneration in acute liver injury [Seite 342]
18.6 - 16.6 Conclusion [Seite 344]
18.7 - References [Seite 344]
19 - 17 Mesenchymal stem cells and the tumor microenvironment [Seite 349]
19.1 - 17.1 Introduction [Seite 349]
19.2 - 17.2 The tumor microenvironment and its role in cancer initiation and progression [Seite 351]
19.3 - 17.3 How do we define MSCs in cancer? [Seite 352]
19.4 - 17.4 What are the roles of MSCs in cancer progression? [Seite 353]
19.4.1 - 17.4.1 Effect of MSCs on tumor cell proliferation [Seite 355]
19.4.2 - 17.4.2 MSCs promote survival [Seite 355]
19.4.3 - 17.4.3 MSCs are proangiogenic [Seite 356]
19.4.4 - 17.4.4 MSCs have an immunosuppressive function [Seite 356]
19.4.5 - 17.4.5 MSCs promote epithelial to mesenchymal transition [Seite 357]
19.5 - 17.5 How do tumor cells communicate with MSCs? [Seite 359]
19.6 - 17.6 Are MSCs recruited by tumor cells? [Seite 361]
19.7 - 17.7 Can we target MSCs in human cancer? [Seite 363]
19.8 - 17.8 Conclusion [Seite 364]
19.9 - References [Seite 364]
20 - 18 Mesenchymal stem cells as a carrier for tumor-targeting therapeutics [Seite 371]
20.1 - 18.1 Introduction [Seite 371]
20.2 - 18.2 Enhanced angiogenesis as a target for tumor therapy [Seite 372]
20.3 - 18.3 Why current therapies are not effective enough [Seite 373]
20.3.1 - 18.3.1 Shortcomings of current anti-angiogenic pharmaceuticals [Seite 374]
20.4 - 18.4 Why mesenchymal stem cells would be useful for tumor targeting [Seite 376]
20.4.1 - 18.4.1 The tumor-homing properties of MSCs [Seite 376]
20.4.2 - 18.4.2 MSCs as a diagnostic tool [Seite 379]
20.4.3 - 18.4.3 Antitumor effects of unmanipulated MSCs [Seite 379]
20.4.4 - 18.4.4 Vesicular communication of MSCs: How MSCs can be used as a drug-delivery vehicle [Seite 380]
20.5 - 18.5 MSCs as a gene product-delivering vehicle [Seite 382]
20.5.1 - 18.5.1 Genetically modified MSCs for therapeutic delivery [Seite 382]
20.5.2 - 18.5.2 Potential for MSCs-delivered anti-angiogenic therapies [Seite 383]
20.5.3 - 18.5.3 MSCs-mediated tumor-homing of oncolytic adenovirus enhances tumor therapy [Seite 384]
20.5.4 - 18.5.4 Delivery of TRAIL by genetically modified MSCs to induce apoptosis [Seite 385]
20.5.5 - 18.5.5 Tumor-specific promoter-driving thymidine kinase (TK) expression for prodrug conversion [Seite 385]
20.6 - 18.6 Methods of therapeutic MSCs administration [Seite 387]
20.7 - 18.7 The advantage of MSCs being immunoprivileged [Seite 388]
20.8 - 18.8 Sources of acquiring MSCs for tumor therapy [Seite 389]
20.9 - 18.9 Remaining challenges for the use of MSCs to deliver therapeutics [Seite 390]
20.9.1 - 18.9.1 The immunoprivileged nature of MSCs [Seite 390]
20.9.2 - 18.9.2 Varying responses to MSCs depending on cancer type, injection site, etc. [Seite 390]
20.9.3 - 18.9.3 Changes in MSCs induced by cancer cells within the tumor microenvironment [Seite 391]
20.10 - 18.10 Summary and prospective [Seite 393]
20.11 - Acknowledgments [Seite 393]
20.12 - References [Seite 394]
21 - 19 Systems biology approach to stem cells, tissues and inflammation [Seite 399]
21.1 - 19.1 Introduction [Seite 399]
21.2 - 19.2 Biological aspects [Seite 400]
21.2.1 - 19.2.1 Cells are the regulatory units [Seite 400]
21.2.2 - 19.2.2 Influence of cell number and phenotype [Seite 401]
21.3 - 19.3 Technological aspects [Seite 401]
21.3.1 - 19.3.1 Technology and type of molecules [Seite 401]
21.3.2 - 19.3.2 When "pictures start moving" [Seite 402]
21.4 - 19.4 Mathematical aspects [Seite 403]
21.4.1 - 19.4.1 Comparative statistics and interpretation [Seite 403]
21.4.2 - 19.4.2 Interpretation based on pre-existing knowledge [Seite 404]
21.4.3 - 19.4.3 Network models [Seite 404]
21.5 - 19.5 Systems biology of differentiation [Seite 406]
21.6 - 19.6 Important tasks [Seite 407]
21.7 - 19.7 Conclusion [Seite 408]
21.8 - References [Seite 409]
22 - Index [Seite 413]