Table of Contents

• 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