Stem Cells in Toxicology and Medicine

Dr. Saura C. Sahu Research Chemist, Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, US Food and Drug Administration. Dr. Sahu is the US Editor for the Journal of Applied Toxicology and the editor of “Hepatotoxicity” (Wiley, 2007), “Toxicogenomics” (Wiley, 2008), “Nanotoxicity” (Wiley, 2009), and “Handbook of Systems Toxicology” (Wiley, 2011).

List of Contributors xx

Preface xxvi

Acknowledgements xxvii

PART I 1

1 Introduction 3
Saura C. Sahu

References 4

2 Application of Stem Cells and iPS Cells in Toxicology 5
Maria Virginia Caballero, Ramon A. Espinoza‐Lewis, and Manila Candiracci

2.1 Introduction 5

2.2 Significance 6

2.3 Stem Cell (SC) Classification 7

2.4 Stem Cells and Pharmacotoxicological Screenings 8

2.5 Industrial Utilization Showcases Stem Cell Technology as a Research Tool 8

2.6 Multipotent Stem Cells (Adult Stem Cells) Characteristics and Current Uses 9

2.7 Mesenchymal Stem Cells (Adult Stem Cells) 10

2.8 Hematopoietic Stem Cells (Adult Stem Cells) 11

2.9 Cardiotoxicity 12

2.10 Hepatotoxicity 15

2.11 Epigenetic Profile 17

2.12 Use of SC and iPSC in Drug Safety 18

2.13 Conclusions and Future Applications 19

Acknowledgments 19

References 19

3 Stem Cells: A Potential Source for High Throughput Screening in Toxicology 26
Harish K Handral, Gopu Sriram, and Tong Cao

3.1 Introduction 26

3.2 Stem Cells 27

3.3 High Throughput Screening (HTS) 31

3.4 Need for a Stem Cell Approach in High Throughput Toxicity Studies 37

3.5 Role of Stem Cells in High Throughput Screening for Toxicity Prediction 38

3.6 Conclusion 40

Acknowledgement 41

Disclosure Statement 41

Author’s Contribution 41

References 41

4 Human Pluripotent Stem Cells for Toxicological Screening 50
Lili Du and Dunjin Chen

4.1 Introduction 50

4.2 The Biological Characteristics of hPSCs 51

4.3 Screening of Embryotoxic Effects using hPSCs 52

4.4 The Potential of hPSC‐Derived Neural Lineages in Neurotoxicology 55

4.5 The Potential of hPSC ‐Derived Cardiomyocytes in Cardiotoxicity 60

4.6 The Potential of hPSC‐Derived Hepatocytes in Hepatotoxicity 62

4.7 Future Challenges and Perspectives for Embryotoxicity and Developmental Toxicity Studies using hPSCs 65

Acknowledgments 66

References 67

5 Effects of Culture Conditions on Maturation of Stem Cell‐Derived Cardiomyocytes 71
Deborah K. Hansen, Amy L. Inselman, and Xi Yang

5.1 Introduction 71

5.2 Lengthening Culture Time 75

5.3 Substrate Stiffness 76

5.4 Structured Substrates 78

5.5 Conclusions 82

Disclaimer 82

References 83

6 Human Stem Cell‐Derived Cardiomyocyte In Vitro Models for Cardiotoxicity Screening 85
Tracy Walker, Kate Harris, Evie Maifoshie, and Khuram Chaudhary

6.1 Introduction 85

6.2 Overview of hPSC‐Derived Cardiomyocytes 88

6.3 Human PSC‐CM Models for Cardiotoxicity Investigations 90

6.4 Conclusions and Future Direction 112

References 112

7 Disease‐Specific Stem Cell Models for Toxicological Screenings and Drug Development 122
Matthias Jung, Juliane‐Susanne Jung, Jovita Schiller, and Insa S. Schroeder

7.1 Evidence for Stem Cell‐Based Drug Development and Toxicological Screenings in Psychiatric Diseases, Cardiovascular Diseases and Diabetes 122

7.2 Disease‐Specific Stem Cell Models for Drug Development in Psychiatric Disorders 127

7.3 Stem Cell Models for Cardiotoxicity and Cardiovascular Disorders 132

7.4 Stem Cell Models for Toxicological Screenings of EDCs 133

References 135

8 Three‐Dimensional Culture Systems and Humanized Liver Models Using Hepatic Stem Cells for Enhanced Toxicity Assessment 145
Ran‐Ran Zhang, Yun‐Wen Zheng, and Hideki Taniguchi

8.1 Introduction 145

8.2 Hepatic Cell Lines and Primary Human Hepatocytes 146

8.3 Embryonic Stem Cells and Induced Pluripotent Stem‐Cell Derived Hepatocytes 147

8.4 Ex Vivo: Three‐Dimensional and Multiple‐Cell Culture System 148

8.5 In Vivo: Humanized Liver Models 149

8.6 Summary 150

Acknowledgments 150

References 150

9 Utilization of In Vitro Neurotoxicity Models in Pre‐Clinical Toxicity Assessment 155
Karin Staflin, Dinah Misner, and Donna Dambach

9.1 Introduction 155

9.2 Current Models of Drug‐Related Clinical Neuropathies and Effects on Electrophysiological Function 159

9.3 Cell Types that Can Potentially Be Used for In Vitro Neurotoxicity Assessment in Drug Development 162

9.4 Utility of iPSC Derived Neurons in In Vitro Safety Assessment 167

9.5 Summary of Key Points for Consideration in Neurotoxicity Assay Development 170

9.6 Concluding Remarks 172

References 172

10 A Human Stem Cell Model for Creating Placental Syncytiotrophoblast, the Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics 179
R. Michael Roberts, Shinichiro Yabe, Ying Yang, and Toshihiko Ezashi

10.1 Introduction 179

10.2 General Features of Placental Structure 180

10.3 The Human Placenta 180

10.4 Human Placental Cells in Toxicology Research 182

10.5 Placental Trophoblast Derived from hESC 183

10.6 Isolation of Syncytial Areas from BAP‐Treated H1 ESC Colonies 185

10.7 Developmental Regulation of Genes Encoding Proteins Potentially Involved in Metabolism of Xenobiotics 185

10.8 Concluding Remarks 191

Acknowledgments 192

References 192

11 The Effects of Endocrine Disruptors on Mesenchymal Stem Cells 196

Marjorie E. Bateman, Amy L. Strong, John McLachlan, Matthew E. Burow, and Bruce A. Bunnell

11.1 Mesenchymal Stem Cells 196

11.2 Endocrine Disruptors 198

11.3 Pesticides 201

11.4 Alkyl Phenols and Derivatives 206

11.5 Bisphenol A 211

11.6 Polychlorinated Biphenyls 216

11.7 Phthalates 221

11.8 Areas for Future Research 225

11.9 Conclusions 226

Abbreviations 226

References 228

12 Epigenetic Landscape in Embryonic Stem Cells 238
Xiaonan Sun, Nicholas Spellmon, Joshua Holcomb, Wen Xue, Chunying Li, and Zhe Yang

12.1 Introduction 238

12.2 DNA Methylation in ESCs 239

12.3 Histone Methylation in ESCs 240

12.4 Chromatin Remodeling and ESCs Regulation 241

12.5 Concluding Remarks 242

Acknowledgements 243

References 243

PART II 247

13 The Effect of Human Pluripotent Stem Cell Platforms on Preclinical Drug Development 249
Kevin G. Chen

13.1 Introduction 249

13.2 Core Signaling Pathways Underlying hPSC Stemness and Differentiation 250

13.3 Basic Components of In Vitro and Ex Vivo hPSC Platforms 251

13.4 Diverse hPSC Culture Platforms for Drug Discovery 252

13.5 Representative Analyses of hPSC‐Based Drug Discovery 255

13.6 Current Challenges and Future Considerations 257

13.7 Concluding Remarks 260

Acknowledgments 260

References 260

14 Generation and Application of 3D Culture Systems in Human Drug Discovery and Medicine 265
H. Rashidi and D.C. Hay

14.1 Introduction 265

14.2 Traditional Scaffold‐Based Tissue Engineering 266

14.3 Scaffold‐Free 3D Culture Systems 269

14.4 Modular Biofabrication 270

14.5 3D Bioprinting 270

14.6 Tissue Modelling and Regenerative Medicine Applications of Pluripotent Stem Cells 272

14.7 Applications in Drug Discovery and Toxicity 275

14.8 Conclusions 278

References 278

15 Characterization and Therapeutic Uses of Adult Mesenchymal Stem Cells 288
Juliann G. Kiang

15.1 Introduction 288

15.2 MSC Characterization 289

15.3 MSCs and Tissue or Organ Therapy 293

15.4 Conclusions 298

Acknowledgments 298

References 298

16 Stem Cell Therapeutics for Cardiovascular Diseases 303
Yuning Hou, Xiaoqing Guan, Shukkur M. Farooq, Xiaonan Sun, Peijun Wang, Zhe Yang,

and Chunying Li

16.1 Introduction 303

16.2 Types of Stem/Progenitor Cell‐Derived Endothelial Cells 304

16.3 EPC and Other Stem/Progenitor Cell Therapy in CVDs 306

16.4 Strategies and Approaches for Enhancing EPC Therapy in CVDs 306

16.5 Concluding Remarks 315

Acknowledgments 316

References 316

17 Stem‐Cell‐Based Therapies for Vascular Regeneration in Peripheral Artery Diseases 324
David M Smadja and Jean‐Sébastien Silvestre

17.1 Sources of Stem Cells for Vascular Regeneration 325

17.2 Canonic Mechanisms Governing Vascular Stem Cells Therapeutic Potential 329

17.3 Stem‐Cell‐Based Therapies in Patients with Peripheral Artery Disease 333

References 337

18 Gene Modified Stem/Progenitor‐Cell Therapy for Ischemic Stroke 347
Yaning Li, Guo‐Yuan Yang, and Yongting Wang

18.1 Introduction 347

18.2 Gene Modified Stem Cells for Ischemic Stroke 348

18.3 Gene Transfer Vectors 354

18.4 Unsolved Issues for Gene‐Modified Stem Cells in Ischemic Stroke 356

18.5 Conclusion 356

Abbreviations 356

Acknowledgments 357

References 357

19 Role of Stem Cells in the Gastrointestinal Tract and in the Development of Cancer 363
Pengyu Huang, Bin Li, and Yun‐Wen Zheng

19.1 Introduction 363

19.2 GI Development and Regeneration 365

19.3 GI Tumorigenesis and Stemness Gene Expression 367

19.4 Toxicants and Other Stress Trigger Epigenetic Changes, Dedifferentiation, and Carcinogenesis 368

19.5 Summary and Perspective 369

Acknowledgments 369

References 370

20 Cancer Stem Cells: Concept, Significance, and Management 375

Haseeb Zubair, Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Saravanakumar Marimuthu, Mary C. Patton, Seema Singh, and Ajay P. Singh

20.1 Introduction 375

20.2 Stem Cells and Cancer: Historical Perspective 376

20.3 Cancer Stem Cells 377

20.4 Identification and Isolation of CSCs 382

20.5 Pathological Significance of Cancer Stem Cells 388

20.6 Pathways Regulating Cancer Stem Cells 389

20.7 Therapeutic Strategies Targeting Cancer Stem Cells 394

20.8 Conclusion and Future Directions 399

References 400

21 Stem Cell Signaling in the Heterogeneous Development of Medulloblastoma 414
Joanna Triscott and Sandra E. Dunn

21.1 Brain Tumor Cancer Stem Cells 414

21.2 Medulloblastoma 416

21.3 Hijacking Cerebellar Development 417

21.4 Molecular Classification of MB 420

21.5 Mouse Models and Cell of Origin 424

21.6 Additional Drivers of MB 425

21.7 Repurposing Off‐Patent Drugs 426

21.8 Emerging Therapies for MB 428

21.9 Conclusion 429

Acknowledgments 429

References 429

22 Induced Pluripotent Stem Cell‐Derived Outer-Blood‐Retinal Barrier for Disease Modeling and Drug Discovery 436
Jun Jeon, Nathan Hotaling, and Kapil Bharti

22.1 Introduction 436

22.2 The Outer Blood‐Retinal Barrier 437

22.3 iPSC‐Based Model of the Outer-Blood‐Retinal-Barrier 439

22.4 iPSC Based OBRB Disease Models 442

22.5 Applications of iPSC‐Based Ocular Disease Models for Drug Discovery 448

22.6 Conclusion and Future Directions 451

References 451

23 Important Considerations in the Therapeutic Application of Stem Cells in Bone

Healing and Regeneration 458
Hoda Elkhenany, Shawn Bourdo, Alexandru Biris, David Anderson, and Madhu Dhar

23.1 Introduction 458

23.2 Stem Cells, Progenitor Cells, Mesenchymal Stem Cells 459

23.3 Scaffolds 461

23.4 Animal Models in Bone Healing and Regeneration 464

23.5 Conclusions and Future Directions 472

References 472

24 Stem Cells from Human Dental Tissue for Regenerative Medicine 481
Junjun Liu and Shangfeng Liu

24.1 Introduction 481

24.2 Dental Stem Cells 482

24.3 Potential Clinical Applications 488

24.4 Safety 492

24.5 Dental Stem Cell Banking 493

24.6 Conclusions and Perspective 494

References 495

25 Stem Cells in the Skin 502
Hongwei Wang, Zhonglan Su, Shiyu Song, Ting Su, Mengyuan Niu, Yaqi Sun, and Hui Xu

25.1 Introduction 502

25.2 Stem Cells in the Skin 503

25.3 Isolation and the Biological Markers of Skin Stem Cells 506

25.4 Skin Stem Cell Niches 508

25.5 Signaling Control of Stem Cell Differentiation 510

25.6 Stem Cells in Skin Aging 514

25.7 Stem Cells in Skin Cancer 516

25.8 Medical Applications of Skin Stem Cells 518

25.9 Conclusions and Future Directions 520

References 521

Author Index 527

Subject Index 529