About the Author xiii
Foreword xv
Preface xvii
Abbreviations xix
About the Companion Website xxxiii
1 Canine Mesenchymal Stem Cells Sources, Properties, and Regulations for Clinical Use 1
1.1 Introduction 1
1.2 Understanding the Stem Cell 3
1.2.1 MSCs Stemness or Stromalness? 4
1.2.2 MSCs Plasticity 6
1.2.3 MSCs Mobilization and Homing 7
1.2.4 Anti-inflammatory and Immunomodulatory Actions 8
1.2.5 Antimicrobial Actions 8
1.3 Sources of Dog MSCs for Proliferation 9
1.4 Why Do We Need to Culture Mesenchymal Stem Cells? 10
1.5 Why to Characterize MSCs? 11
1.6 Factors Affecting MSCs Therapeutic Outcome 12
1.7 Stem Cell Regulations in Research and Therapeutics 13
References 15
2 Osteoarthritis 27
2.1 Introduction 27
2.2 Predisposing Factors 28
2.3 OA Pathogenesis 30
2.3.1 OA Mediated Through Cartilage 30
2.3.2 OA Mediated Through Synovitis 34
2.3.3 Subchondral Bone Involvement 36
2.4 MSCs and Their Potential Therapeutic Role in OA 37
2.4.1 MSCs Chondrogenic Studies and Ex Vivo Findings 37
2.4.1.1 Culture Technique 38
2.4.1.2 Local Microenvironment 39
2.4.1.3 Source of MSCs 39
2.4.1.4 MSCs Transplantation Techniques and Drug Reactions 39
2.4.1.5 Therapeutic Properties of MSCs 40
2.5 In Vivo MSCs Studies 42
2.5.1 Preclinical Experimental Studies 42
2.5.1.1 Chondral Lesions 42
2.5.1.2 Osteochondral Defects 46
2.5.1.3 Cruciate Ligament Resection Model 51
2.5.1.4 Meniscectomy Model 54
2.5.2 Clinical Studies 55
2.5.2.1 Hip Joint OA 56
2.5.2.2 Elbow OA 61
2.5.2.3 Stifle Joint OA 66
2.5.2.4 Multiple Joint OA 66
2.5.2.5 Hip Dysplasia Induced OA 72
References 73
3 MSCs in Canine Bone Tissue Engineering 97
3.1 Introduction 97
3.2 Mesenchymal Stem Cells and Bone Regeneration 99
3.2.1 MSCs In Vitro Osteogenesis 100
3.2.1.1 Osteogenic Growth Factors/Chemicals 101
3.2.1.2 Effect of Source 103
3.2.1.3 Scaffold and MSCs Osteogenesis 105
3.2.1.4 Breed-Wise Differences 106
3.2.2 MSCs Osteogenesis 107
3.3 In Vivo Studies 107
3.3.1 Preclinical Experimental Studies in Dogs 108
3.3.1.1 Femoral Bone Defect Model 109
3.3.1.2 Radial Bone Defect Model 117
3.3.1.3 Ulnar Bone Defect Model 118
3.3.1.4 Tibial Bone Defect Model 119
3.3.1.5 Mandibular Bone Defect Models 120
3.3.2 Dog In Vivo Clinical Studies 125
3.3.2.1 Augmentation of Normal Bone Healing 128
3.3.2.2 Nonunion Radial Fracture 128
3.3.2.3 Nonunion Radial/Ulnar Fracture 129
3.3.2.4 Nonunion Femoral Fracture 130
References 131
4 Muscle, Tendon, and Ligament Affections 149
4.1 Introduction 149
4.2 Why Mesenchymal Stem Cells and Not Tendon Stem/Progenitor Cells (TSPCs)? 152
4.2.1 Tenogenic Markers 154
4.2.2 In Vitro Studies on MSCs Tenogenesis 155
4.2.2.1 Tenogenic Differentiation 155
4.2.2.2 In Vitro Tendon Healing Model 158
4.3 In Vivo Studies 160
4.3.1 Tendon Repair Models 160
4.3.1.1 Intrasynovial Second and Fifth Flexor Digitorum Profundus Model 160
4.3.1.2 Rotator Cuff Injury Model 165
4.3.1.3 Achilles Tendon Model 167
4.3.2 Clinical Tendinopathies 167
4.3.3 Ligament Repair Models 170
4.3.3.1 Partial CrCL Tear Studies 171
4.3.3.2 Complete CrCL Tear Studies 173
4.4 Muscle Studies 175
4.4.1 MSCs In Vitro Myogenic Differentiation 175
4.4.2 In Vivo Clinical Muscle Injury Studies 176
4.4.3 Duchenne’s Muscle Dystrophy (DMD) 179
References 180
5 Peripheral Nerve Affections 197
5.1 Introduction 197
5.2 Peripheral Nerve Injury 199
5.2.1 Natural Recovery of Peripheral Nerves 201
5.2.1.1 Role of Schwann Cells and Macrophages 203
5.2.2 Surgical Procedure and Limitations Thereof 205
5.3 Why MSCs and Not Schwann Cells for Nerve Regeneration 206
5.4 In Vivo Peripheral Nerve Injury Studies 207
5.4.1 Dog Peripheral Nerve Resection Models 209
5.4.1.1 Sciatic Nerve Repair 209
5.4.1.2 Facial Nerve Repair 212
5.4.1.3 Ulnar Nerve 214
References 216
6 Central Nervous System Affections 225
6.1 Introduction 225
6.2 CNS Intrinsic Regeneration Potential 226
6.3 Exogenous Stem Cell Therapy 227
6.3.1 In Vitro MSCs Neurogenic Studies 228
6.3.1.1 Neural-Induced MSCs Morphology and Expression 228
6.3.1.2 Expression and Secretion Potential of Neural-Induced MSCs 229
6.3.2 Contradicted View-Point Toward MSCs Neural-Like Differentiation 233
6.3.3 In Vivo Studies 234
6.3.3.1 MSCs Therapeutic Mechanisms 235
6.3.3.2 Meningoencephalomyelitis of Unknown Origin (MUO) 237
6.3.3.3 Canine Distemper (CD) 238
6.3.3.4 Spinal Cord Injury (SCI) 242
References 270
7 Myocardial and Valvular Diseases 287
7.1 Introduction 287
7.2 Why MSCs in Cardiac Diseases? 288
7.2.1 Differentiation 289
7.2.1.1 Microenvironment Modulation 289
7.2.1.2 Genetic Modulation 292
7.2.2 MSCs Stromalness for Cardiac Regeneration 294
7.3 In Vivo MSCs Therapeutic Studies in Dogs 296
7.3.1 MSCs Transplantation 298
7.3.2 Cellular Concentration and Transplantation Rate 299
7.3.3 Cellular Distribution 300
7.3.4 Cellular Differentiation 301
7.3.5 Myocardial Infarction (MI) 302
7.3.5.1 Acute mi 303
7.3.5.2 Subacute mi 307
7.3.5.3 Chronic mi 308
7.3.6 MSCs as Biological Pacemaker 310
7.3.6.1 In Vivo Studies 311
7.3.7 Dilatation Cardiomyopathy (DCM) 314
7.3.7.1 In Vivo Studies 315
7.3.8 Chronic Chagas Cardiomyopathy 318
7.3.9 Valvular Diseases 319
References 321
8 Oral and Esophageal Affections 341
8.1 Introduction 341
8.2 Oral Mucosal Ulcers 344
8.3 Periodontal Disease 347
8.3.1 Fenestration Defects 355
8.3.2 Intrabony Defects 356
8.3.3 Furcation Defects 358
8.4 Maxillary Alveolar Bone Cleft Model 359
8.5 Peri-implant Defect Models 360
8.6 Esophagus 362
8.6.1 Esophageal Ulceration 363
8.6.2 Esophageal Resection 365
References 366
9 Inflammatory Bowel Disease and Anal Furunculosis 377
9.1 Introduction 377
9.2 Why Mesenchymal Stem Cells 382
9.3 In Vivo Studies 384
9.3.1 Inflammatory Bowel Disease (IBD) 384
9.3.2 Anal Furunculosis (AF) 388
References 389
10 Liver Affections 397
10.1 Introduction 397
10.2 Regenerative Medicine in Canine Hepatology 398
10.2.1 Why Mesenchymal Stem Cells for Liver Regeneration 399
10.2.2 In Vitro MSCs Hepatocyte-Like Cell Differentiation 400
10.2.2.1 Microenvironment Modifications 400
10.2.2.2 3D Culture of MSCs for Hepatocyte-Like Cell Differentiation 402
10.2.2.3 Genetic Manipulation of MSCs 403
10.3 In Vivo Liver Regenerative Studies 404
10.3.1 Dog Hepatic Injury Models 405
10.3.1.1 Acute Liver Injury Models 405
10.3.1.2 Hepatic Fibrosis Models 407
10.4 Hepatocutaneous Syndrome 409
References 411
11 Lung Affections 419
11.1 Introduction 419
11.2 MSCs Potential Therapeutic Effects 421
11.3 In Vivo Studies 423
11.3.1 Acute Respiratory Distress Syndrome (ARDS) 423
11.3.2 Radiation-Induced Lung Injury 427
References 428
12 Renal Insufficiency and Urinary Bladder Affections 435
12.1 Introduction 435
12.2 In Vitro Renal Studies 437
12.3 In Vivo Renal Studies 441
12.3.1 Experimental Studies 441
12.3.1.1 Drug-Induced Acute Kidney Injury 444
12.3.1.2 Ischemic AKI 446
12.3.1.3 Chronic Kidney Disease Model 448
12.3.2 Clinical Studies 449
12.3.2.1 Chronic Kidney Disease 449
12.3.2.2 Renal Fanconi Syndrome 449
12.4 Urinary Bladder 450
12.4.1 In Vivo Studies 451
References 453
13 Skin Wounds and Atopic Dermatitis 461
13.1 Introduction 461
13.2 In Vivo Skin Wound-Healing Studies Using MSCs 462
13.2.1 Preclinical Experimental Studies 463
13.2.2 Clinical Studies 466
13.2.2.1 Acute Wounds 466
13.2.2.2 Chronic Wounds 470
13.3 Atopic Dermatitis (AD) 472
13.3.1 Ex Vivo Studies 473
13.3.2 In Vivo Studies 474
13.3.2.1 Experimental Studies 474
13.3.2.2 Clinical Studies 477
References 479
14 Diabetes 487
14.1 Introduction 487
14.2 In Vitro Studies 490
14.2.1 MSCs Trans-differentiation into IPCs 491
14.2.1.1 Microenvironment Manipulation 491
14.2.1.2 Genetic Manipulation 496
14.2.1.3 Combined Microenvironment and Genetic Modifications 497
14.2.1.4 Secretome-Based Pro-islet Cell-Like Response 498
14.2.2 MSCs Versus PSCs to Form IPCs 498
14.3 In Vivo Studies 499
14.3.1 Experimental Studies 500
14.3.1.1 Transplantation of Transfected Cells 500
14.3.1.2 Transplantation of Chemical-Induced Cells 502
14.3.2 Clinical Studies 503
References 506
15 Corneal Ulcers and Keratoconjunctivitis Sicca 517
15.1 Introduction 517
15.2 Mesenchymal Stem Cells (MSCs) Versus Corneal/Limbal Stem Cells 518
15.3 Corneal Affections 521
15.3.1 Corneal Ulcer 522
15.3.1.1 In Vivo Studies 523
15.3.1.2 Corneal Superficial Keratitis (Pannus) 525
15.3.1.3 Descemetocele 526
15.4 Keratoconjunctivitis Sicca (KCS) 527
15.4.1 Route of MSCs Transplantation 530
15.4.2 Therapeutic Outcome 531
References 532
Index 543