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).

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• List of Contributors xxPreface xxviAcknowledgements xxviiPART I 11 Introduction 3Saura C. SahuReferences 42 Application of Stem Cells and iPS Cells in Toxicology 5Maria Virginia Caballero, Ramon A. Espinoza‐Lewis, and Manila Candiracci2.1 Introduction 52.2 Significance 62.3 Stem Cell (SC) Classification 72.4 Stem Cells and Pharmacotoxicological Screenings 82.5 Industrial Utilization Showcases Stem Cell Technology as a Research Tool 82.6 Multipotent Stem Cells (Adult Stem Cells) Characteristics and Current Uses 92.7 Mesenchymal Stem Cells (Adult Stem Cells) 102.8 Hematopoietic Stem Cells (Adult Stem Cells) 112.9 Cardiotoxicity 122.10 Hepatotoxicity 152.11 Epigenetic Profile 172.12 Use of SC and iPSC in Drug Safety 182.13 Conclusions and Future Applications 19Acknowledgments 19References 193 Stem Cells: A Potential Source for High Throughput Screening in Toxicology 26Harish K Handral, Gopu Sriram, and Tong Cao3.1 Introduction 263.2 Stem Cells 273.3 High Throughput Screening (HTS) 313.4 Need for a Stem Cell Approach in High Throughput Toxicity Studies 373.5 Role of Stem Cells in High Throughput Screening for Toxicity Prediction 383.6 Conclusion 40Acknowledgement 41Disclosure Statement 41Author’s Contribution 41References 414 Human Pluripotent Stem Cells for Toxicological Screening 50Lili Du and Dunjin Chen4.1 Introduction 504.2 The Biological Characteristics of hPSCs 514.3 Screening of Embryotoxic Effects using hPSCs 524.4 The Potential of hPSC‐Derived Neural Lineages in Neurotoxicology 554.5 The Potential of hPSC ‐Derived Cardiomyocytes in Cardiotoxicity 604.6 The Potential of hPSC‐Derived Hepatocytes in Hepatotoxicity 624.7 Future Challenges and Perspectives for Embryotoxicity and Developmental Toxicity Studies using hPSCs 65Acknowledgments 66References 675 Effects of Culture Conditions on Maturation of Stem Cell‐Derived Cardiomyocytes 71Deborah K. Hansen, Amy L. Inselman, and Xi Yang5.1 Introduction 715.2 Lengthening Culture Time 755.3 Substrate Stiffness 765.4 Structured Substrates 785.5 Conclusions 82Disclaimer 82References 836 Human Stem Cell‐Derived Cardiomyocyte In Vitro Models for Cardiotoxicity Screening 85Tracy Walker, Kate Harris, Evie Maifoshie, and Khuram Chaudhary6.1 Introduction 856.2 Overview of hPSC‐Derived Cardiomyocytes 886.3 Human PSC‐CM Models for Cardiotoxicity Investigations 906.4 Conclusions and Future Direction 112References 1127 Disease‐Specific Stem Cell Models for Toxicological Screenings and Drug Development 122Matthias Jung, Juliane‐Susanne Jung, Jovita Schiller, and Insa S. Schroeder7.1 Evidence for Stem Cell‐Based Drug Development and Toxicological Screenings in Psychiatric Diseases, Cardiovascular Diseases and Diabetes 1227.2 Disease‐Specific Stem Cell Models for Drug Development in Psychiatric Disorders 1277.3 Stem Cell Models for Cardiotoxicity and Cardiovascular Disorders 1327.4 Stem Cell Models for Toxicological Screenings of EDCs 133References 1358 Three‐Dimensional Culture Systems and Humanized Liver Models Using Hepatic Stem Cells for Enhanced Toxicity Assessment 145Ran‐Ran Zhang, Yun‐Wen Zheng, and Hideki Taniguchi8.1 Introduction 1458.2 Hepatic Cell Lines and Primary Human Hepatocytes 1468.3 Embryonic Stem Cells and Induced Pluripotent Stem‐Cell Derived Hepatocytes 1478.4 Ex Vivo: Three‐Dimensional and Multiple‐Cell Culture System 1488.5 In Vivo: Humanized Liver Models 1498.6 Summary 150Acknowledgments 150References 1509 Utilization of In Vitro Neurotoxicity Models in Pre‐Clinical Toxicity Assessment 155Karin Staflin, Dinah Misner, and Donna Dambach9.1 Introduction 1559.2 Current Models of Drug‐Related Clinical Neuropathies and Effects on Electrophysiological Function 1599.3 Cell Types that Can Potentially Be Used for In Vitro Neurotoxicity Assessment in Drug Development 1629.4 Utility of iPSC Derived Neurons in In Vitro Safety Assessment 1679.5 Summary of Key Points for Consideration in Neurotoxicity Assay Development 1709.6 Concluding Remarks 172References 17210 A Human Stem Cell Model for Creating Placental Syncytiotrophoblast, the Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics 179R. Michael Roberts, Shinichiro Yabe, Ying Yang, and Toshihiko Ezashi10.1 Introduction 17910.2 General Features of Placental Structure 18010.3 The Human Placenta 18010.4 Human Placental Cells in Toxicology Research 18210.5 Placental Trophoblast Derived from hESC 18310.6 Isolation of Syncytial Areas from BAP‐Treated H1 ESC Colonies 18510.7 Developmental Regulation of Genes Encoding Proteins Potentially Involved in Metabolism of Xenobiotics 18510.8 Concluding Remarks 191Acknowledgments 192References 19211 The Effects of Endocrine Disruptors on Mesenchymal Stem Cells 196Marjorie E. Bateman, Amy L. Strong, John McLachlan, Matthew E. Burow, and Bruce A. Bunnell11.1 Mesenchymal Stem Cells 19611.2 Endocrine Disruptors 19811.3 Pesticides 20111.4 Alkyl Phenols and Derivatives 20611.5 Bisphenol A 21111.6 Polychlorinated Biphenyls 21611.7 Phthalates 22111.8 Areas for Future Research 22511.9 Conclusions 226Abbreviations 226References 22812 Epigenetic Landscape in Embryonic Stem Cells 238Xiaonan Sun, Nicholas Spellmon, Joshua Holcomb, Wen Xue, Chunying Li, and Zhe Yang12.1 Introduction 23812.2 DNA Methylation in ESCs 23912.3 Histone Methylation in ESCs 24012.4 Chromatin Remodeling and ESCs Regulation 24112.5 Concluding Remarks 242Acknowledgements 243References 243PART II 24713 The Effect of Human Pluripotent Stem Cell Platforms on Preclinical Drug Development 249Kevin G. Chen13.1 Introduction 24913.2 Core Signaling Pathways Underlying hPSC Stemness and Differentiation 25013.3 Basic Components of In Vitro and Ex Vivo hPSC Platforms 25113.4 Diverse hPSC Culture Platforms for Drug Discovery 25213.5 Representative Analyses of hPSC‐Based Drug Discovery 25513.6 Current Challenges and Future Considerations 25713.7 Concluding Remarks 260Acknowledgments 260References 26014 Generation and Application of 3D Culture Systems in Human Drug Discovery and Medicine 265H. Rashidi and D.C. Hay14.1 Introduction 26514.2 Traditional Scaffold‐Based Tissue Engineering 26614.3 Scaffold‐Free 3D Culture Systems 26914.4 Modular Biofabrication 27014.5 3D Bioprinting 27014.6 Tissue Modelling and Regenerative Medicine Applications of Pluripotent Stem Cells 27214.7 Applications in Drug Discovery and Toxicity 27514.8 Conclusions 278References 27815 Characterization and Therapeutic Uses of Adult Mesenchymal Stem Cells 288Juliann G. Kiang15.1 Introduction 28815.2 MSC Characterization 28915.3 MSCs and Tissue or Organ Therapy 29315.4 Conclusions 298Acknowledgments 298References 29816 Stem Cell Therapeutics for Cardiovascular Diseases 303Yuning Hou, Xiaoqing Guan, Shukkur M. Farooq, Xiaonan Sun, Peijun Wang, Zhe Yang,and Chunying Li16.1 Introduction 30316.2 Types of Stem/Progenitor Cell‐Derived Endothelial Cells 30416.3 EPC and Other Stem/Progenitor Cell Therapy in CVDs 30616.4 Strategies and Approaches for Enhancing EPC Therapy in CVDs 30616.5 Concluding Remarks 315Acknowledgments 316References 31617 Stem‐Cell‐Based Therapies for Vascular Regeneration in Peripheral Artery Diseases 324David M Smadja and Jean‐Sébastien Silvestre17.1 Sources of Stem Cells for Vascular Regeneration 32517.2 Canonic Mechanisms Governing Vascular Stem Cells Therapeutic Potential 32917.3 Stem‐Cell‐Based Therapies in Patients with Peripheral Artery Disease 333References 33718 Gene Modified Stem/Progenitor‐Cell Therapy for Ischemic Stroke 347Yaning Li, Guo‐Yuan Yang, and Yongting Wang18.1 Introduction 34718.2 Gene Modified Stem Cells for Ischemic Stroke 34818.3 Gene Transfer Vectors 35418.4 Unsolved Issues for Gene‐Modified Stem Cells in Ischemic Stroke 35618.5 Conclusion 356Abbreviations 356Acknowledgments 357References 35719 Role of Stem Cells in the Gastrointestinal Tract and in the Development of Cancer 363Pengyu Huang, Bin Li, and Yun‐Wen Zheng19.1 Introduction 36319.2 GI Development and Regeneration 36519.3 GI Tumorigenesis and Stemness Gene Expression 36719.4 Toxicants and Other Stress Trigger Epigenetic Changes, Dedifferentiation, and Carcinogenesis 36819.5 Summary and Perspective 369Acknowledgments 369References 37020 Cancer Stem Cells: Concept, Significance, and Management 375Haseeb Zubair, Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Saravanakumar Marimuthu, Mary C. Patton, Seema Singh, and Ajay P. Singh20.1 Introduction 37520.2 Stem Cells and Cancer: Historical Perspective 37620.3 Cancer Stem Cells 37720.4 Identification and Isolation of CSCs 38220.5 Pathological Significance of Cancer Stem Cells 38820.6 Pathways Regulating Cancer Stem Cells 38920.7 Therapeutic Strategies Targeting Cancer Stem Cells 39420.8 Conclusion and Future Directions 399References 40021 Stem Cell Signaling in the Heterogeneous Development of Medulloblastoma 414Joanna Triscott and Sandra E. Dunn21.1 Brain Tumor Cancer Stem Cells 41421.2 Medulloblastoma 41621.3 Hijacking Cerebellar Development 41721.4 Molecular Classification of MB 42021.5 Mouse Models and Cell of Origin 42421.6 Additional Drivers of MB 42521.7 Repurposing Off‐Patent Drugs 42621.8 Emerging Therapies for MB 42821.9 Conclusion 429Acknowledgments 429References 42922 Induced Pluripotent Stem Cell‐Derived Outer-Blood‐Retinal Barrier for Disease Modeling and Drug Discovery 436Jun Jeon, Nathan Hotaling, and Kapil Bharti22.1 Introduction 43622.2 The Outer Blood‐Retinal Barrier 43722.3 iPSC‐Based Model of the Outer-Blood‐Retinal-Barrier 43922.4 iPSC Based OBRB Disease Models 44222.5 Applications of iPSC‐Based Ocular Disease Models for Drug Discovery 44822.6 Conclusion and Future Directions 451References 45123 Important Considerations in the Therapeutic Application of Stem Cells in BoneHealing and Regeneration 458Hoda Elkhenany, Shawn Bourdo, Alexandru Biris, David Anderson, and Madhu Dhar23.1 Introduction 45823.2 Stem Cells, Progenitor Cells, Mesenchymal Stem Cells 45923.3 Scaffolds 46123.4 Animal Models in Bone Healing and Regeneration 46423.5 Conclusions and Future Directions 472References 47224 Stem Cells from Human Dental Tissue for Regenerative Medicine 481Junjun Liu and Shangfeng Liu24.1 Introduction 48124.2 Dental Stem Cells 48224.3 Potential Clinical Applications 48824.4 Safety 49224.5 Dental Stem Cell Banking 49324.6 Conclusions and Perspective 494References 49525 Stem Cells in the Skin 502Hongwei Wang, Zhonglan Su, Shiyu Song, Ting Su, Mengyuan Niu, Yaqi Sun, and Hui Xu25.1 Introduction 50225.2 Stem Cells in the Skin 50325.3 Isolation and the Biological Markers of Skin Stem Cells 50625.4 Skin Stem Cell Niches 50825.5 Signaling Control of Stem Cell Differentiation 51025.6 Stem Cells in Skin Aging 51425.7 Stem Cells in Skin Cancer 51625.8 Medical Applications of Skin Stem Cells 51825.9 Conclusions and Future Directions 520References 521Author Index 527Subject Index 529

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).

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• List of Contributors xxPreface xxviAcknowledgements xxviiPART I 11 Introduction 3Saura C. SahuReferences 42 Application of Stem Cells and iPS Cells in Toxicology 5Maria Virginia Caballero, Ramon A. Espinoza‐Lewis, and Manila Candiracci2.1 Introduction 52.2 Significance 62.3 Stem Cell (SC) Classification 72.4 Stem Cells and Pharmacotoxicological Screenings 82.5 Industrial Utilization Showcases Stem Cell Technology as a Research Tool 82.6 Multipotent Stem Cells (Adult Stem Cells) Characteristics and Current Uses 92.7 Mesenchymal Stem Cells (Adult Stem Cells) 102.8 Hematopoietic Stem Cells (Adult Stem Cells) 112.9 Cardiotoxicity 122.10 Hepatotoxicity 152.11 Epigenetic Profile 172.12 Use of SC and iPSC in Drug Safety 182.13 Conclusions and Future Applications 19Acknowledgments 19References 193 Stem Cells: A Potential Source for High Throughput Screening in Toxicology 26Harish K Handral, Gopu Sriram, and Tong Cao3.1 Introduction 263.2 Stem Cells 273.3 High Throughput Screening (HTS) 313.4 Need for a Stem Cell Approach in High Throughput Toxicity Studies 373.5 Role of Stem Cells in High Throughput Screening for Toxicity Prediction 383.6 Conclusion 40Acknowledgement 41Disclosure Statement 41Author’s Contribution 41References 414 Human Pluripotent Stem Cells for Toxicological Screening 50Lili Du and Dunjin Chen4.1 Introduction 504.2 The Biological Characteristics of hPSCs 514.3 Screening of Embryotoxic Effects using hPSCs 524.4 The Potential of hPSC‐Derived Neural Lineages in Neurotoxicology 554.5 The Potential of hPSC ‐Derived Cardiomyocytes in Cardiotoxicity 604.6 The Potential of hPSC‐Derived Hepatocytes in Hepatotoxicity 624.7 Future Challenges and Perspectives for Embryotoxicity and Developmental Toxicity Studies using hPSCs 65Acknowledgments 66References 675 Effects of Culture Conditions on Maturation of Stem Cell‐Derived Cardiomyocytes 71Deborah K. Hansen, Amy L. Inselman, and Xi Yang5.1 Introduction 715.2 Lengthening Culture Time 755.3 Substrate Stiffness 765.4 Structured Substrates 785.5 Conclusions 82Disclaimer 82References 836 Human Stem Cell‐Derived Cardiomyocyte In Vitro Models for Cardiotoxicity Screening 85Tracy Walker, Kate Harris, Evie Maifoshie, and Khuram Chaudhary6.1 Introduction 856.2 Overview of hPSC‐Derived Cardiomyocytes 886.3 Human PSC‐CM Models for Cardiotoxicity Investigations 906.4 Conclusions and Future Direction 112References 1127 Disease‐Specific Stem Cell Models for Toxicological Screenings and Drug Development 122Matthias Jung, Juliane‐Susanne Jung, Jovita Schiller, and Insa S. Schroeder7.1 Evidence for Stem Cell‐Based Drug Development and Toxicological Screenings in Psychiatric Diseases, Cardiovascular Diseases and Diabetes 1227.2 Disease‐Specific Stem Cell Models for Drug Development in Psychiatric Disorders 1277.3 Stem Cell Models for Cardiotoxicity and Cardiovascular Disorders 1327.4 Stem Cell Models for Toxicological Screenings of EDCs 133References 1358 Three‐Dimensional Culture Systems and Humanized Liver Models Using Hepatic Stem Cells for Enhanced Toxicity Assessment 145Ran‐Ran Zhang, Yun‐Wen Zheng, and Hideki Taniguchi8.1 Introduction 1458.2 Hepatic Cell Lines and Primary Human Hepatocytes 1468.3 Embryonic Stem Cells and Induced Pluripotent Stem‐Cell Derived Hepatocytes 1478.4 Ex Vivo: Three‐Dimensional and Multiple‐Cell Culture System 1488.5 In Vivo: Humanized Liver Models 1498.6 Summary 150Acknowledgments 150References 1509 Utilization of In Vitro Neurotoxicity Models in Pre‐Clinical Toxicity Assessment 155Karin Staflin, Dinah Misner, and Donna Dambach9.1 Introduction 1559.2 Current Models of Drug‐Related Clinical Neuropathies and Effects on Electrophysiological Function 1599.3 Cell Types that Can Potentially Be Used for In Vitro Neurotoxicity Assessment in Drug Development 1629.4 Utility of iPSC Derived Neurons in In Vitro Safety Assessment 1679.5 Summary of Key Points for Consideration in Neurotoxicity Assay Development 1709.6 Concluding Remarks 172References 17210 A Human Stem Cell Model for Creating Placental Syncytiotrophoblast, the Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics 179R. Michael Roberts, Shinichiro Yabe, Ying Yang, and Toshihiko Ezashi10.1 Introduction 17910.2 General Features of Placental Structure 18010.3 The Human Placenta 18010.4 Human Placental Cells in Toxicology Research 18210.5 Placental Trophoblast Derived from hESC 18310.6 Isolation of Syncytial Areas from BAP‐Treated H1 ESC Colonies 18510.7 Developmental Regulation of Genes Encoding Proteins Potentially Involved in Metabolism of Xenobiotics 18510.8 Concluding Remarks 191Acknowledgments 192References 19211 The Effects of Endocrine Disruptors on Mesenchymal Stem Cells 196Marjorie E. Bateman, Amy L. Strong, John McLachlan, Matthew E. Burow, and Bruce A. Bunnell11.1 Mesenchymal Stem Cells 19611.2 Endocrine Disruptors 19811.3 Pesticides 20111.4 Alkyl Phenols and Derivatives 20611.5 Bisphenol A 21111.6 Polychlorinated Biphenyls 21611.7 Phthalates 22111.8 Areas for Future Research 22511.9 Conclusions 226Abbreviations 226References 22812 Epigenetic Landscape in Embryonic Stem Cells 238Xiaonan Sun, Nicholas Spellmon, Joshua Holcomb, Wen Xue, Chunying Li, and Zhe Yang12.1 Introduction 23812.2 DNA Methylation in ESCs 23912.3 Histone Methylation in ESCs 24012.4 Chromatin Remodeling and ESCs Regulation 24112.5 Concluding Remarks 242Acknowledgements 243References 243PART II 24713 The Effect of Human Pluripotent Stem Cell Platforms on Preclinical Drug Development 249Kevin G. Chen13.1 Introduction 24913.2 Core Signaling Pathways Underlying hPSC Stemness and Differentiation 25013.3 Basic Components of In Vitro and Ex Vivo hPSC Platforms 25113.4 Diverse hPSC Culture Platforms for Drug Discovery 25213.5 Representative Analyses of hPSC‐Based Drug Discovery 25513.6 Current Challenges and Future Considerations 25713.7 Concluding Remarks 260Acknowledgments 260References 26014 Generation and Application of 3D Culture Systems in Human Drug Discovery and Medicine 265H. Rashidi and D.C. Hay14.1 Introduction 26514.2 Traditional Scaffold‐Based Tissue Engineering 26614.3 Scaffold‐Free 3D Culture Systems 26914.4 Modular Biofabrication 27014.5 3D Bioprinting 27014.6 Tissue Modelling and Regenerative Medicine Applications of Pluripotent Stem Cells 27214.7 Applications in Drug Discovery and Toxicity 27514.8 Conclusions 278References 27815 Characterization and Therapeutic Uses of Adult Mesenchymal Stem Cells 288Juliann G. Kiang15.1 Introduction 28815.2 MSC Characterization 28915.3 MSCs and Tissue or Organ Therapy 29315.4 Conclusions 298Acknowledgments 298References 29816 Stem Cell Therapeutics for Cardiovascular Diseases 303Yuning Hou, Xiaoqing Guan, Shukkur M. Farooq, Xiaonan Sun, Peijun Wang, Zhe Yang,and Chunying Li16.1 Introduction 30316.2 Types of Stem/Progenitor Cell‐Derived Endothelial Cells 30416.3 EPC and Other Stem/Progenitor Cell Therapy in CVDs 30616.4 Strategies and Approaches for Enhancing EPC Therapy in CVDs 30616.5 Concluding Remarks 315Acknowledgments 316References 31617 Stem‐Cell‐Based Therapies for Vascular Regeneration in Peripheral Artery Diseases 324David M Smadja and Jean‐Sébastien Silvestre17.1 Sources of Stem Cells for Vascular Regeneration 32517.2 Canonic Mechanisms Governing Vascular Stem Cells Therapeutic Potential 32917.3 Stem‐Cell‐Based Therapies in Patients with Peripheral Artery Disease 333References 33718 Gene Modified Stem/Progenitor‐Cell Therapy for Ischemic Stroke 347Yaning Li, Guo‐Yuan Yang, and Yongting Wang18.1 Introduction 34718.2 Gene Modified Stem Cells for Ischemic Stroke 34818.3 Gene Transfer Vectors 35418.4 Unsolved Issues for Gene‐Modified Stem Cells in Ischemic Stroke 35618.5 Conclusion 356Abbreviations 356Acknowledgments 357References 35719 Role of Stem Cells in the Gastrointestinal Tract and in the Development of Cancer 363Pengyu Huang, Bin Li, and Yun‐Wen Zheng19.1 Introduction 36319.2 GI Development and Regeneration 36519.3 GI Tumorigenesis and Stemness Gene Expression 36719.4 Toxicants and Other Stress Trigger Epigenetic Changes, Dedifferentiation, and Carcinogenesis 36819.5 Summary and Perspective 369Acknowledgments 369References 37020 Cancer Stem Cells: Concept, Significance, and Management 375Haseeb Zubair, Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Saravanakumar Marimuthu, Mary C. Patton, Seema Singh, and Ajay P. Singh20.1 Introduction 37520.2 Stem Cells and Cancer: Historical Perspective 37620.3 Cancer Stem Cells 37720.4 Identification and Isolation of CSCs 38220.5 Pathological Significance of Cancer Stem Cells 38820.6 Pathways Regulating Cancer Stem Cells 38920.7 Therapeutic Strategies Targeting Cancer Stem Cells 39420.8 Conclusion and Future Directions 399References 40021 Stem Cell Signaling in the Heterogeneous Development of Medulloblastoma 414Joanna Triscott and Sandra E. Dunn21.1 Brain Tumor Cancer Stem Cells 41421.2 Medulloblastoma 41621.3 Hijacking Cerebellar Development 41721.4 Molecular Classification of MB 42021.5 Mouse Models and Cell of Origin 42421.6 Additional Drivers of MB 42521.7 Repurposing Off‐Patent Drugs 42621.8 Emerging Therapies for MB 42821.9 Conclusion 429Acknowledgments 429References 42922 Induced Pluripotent Stem Cell‐Derived Outer-Blood‐Retinal Barrier for Disease Modeling and Drug Discovery 436Jun Jeon, Nathan Hotaling, and Kapil Bharti22.1 Introduction 43622.2 The Outer Blood‐Retinal Barrier 43722.3 iPSC‐Based Model of the Outer-Blood‐Retinal-Barrier 43922.4 iPSC Based OBRB Disease Models 44222.5 Applications of iPSC‐Based Ocular Disease Models for Drug Discovery 44822.6 Conclusion and Future Directions 451References 45123 Important Considerations in the Therapeutic Application of Stem Cells in BoneHealing and Regeneration 458Hoda Elkhenany, Shawn Bourdo, Alexandru Biris, David Anderson, and Madhu Dhar23.1 Introduction 45823.2 Stem Cells, Progenitor Cells, Mesenchymal Stem Cells 45923.3 Scaffolds 46123.4 Animal Models in Bone Healing and Regeneration 46423.5 Conclusions and Future Directions 472References 47224 Stem Cells from Human Dental Tissue for Regenerative Medicine 481Junjun Liu and Shangfeng Liu24.1 Introduction 48124.2 Dental Stem Cells 48224.3 Potential Clinical Applications 48824.4 Safety 49224.5 Dental Stem Cell Banking 49324.6 Conclusions and Perspective 494References 49525 Stem Cells in the Skin 502Hongwei Wang, Zhonglan Su, Shiyu Song, Ting Su, Mengyuan Niu, Yaqi Sun, and Hui Xu25.1 Introduction 50225.2 Stem Cells in the Skin 50325.3 Isolation and the Biological Markers of Skin Stem Cells 50625.4 Skin Stem Cell Niches 50825.5 Signaling Control of Stem Cell Differentiation 51025.6 Stem Cells in Skin Aging 51425.7 Stem Cells in Skin Cancer 51625.8 Medical Applications of Skin Stem Cells 51825.9 Conclusions and Future Directions 520References 521Author Index 527Subject Index 529

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).

Select Guide Rating

• List of Contributors xxPreface xxviAcknowledgements xxviiPART I 11 Introduction 3Saura C. SahuReferences 42 Application of Stem Cells and iPS Cells in Toxicology 5Maria Virginia Caballero, Ramon A. Espinoza‐Lewis, and Manila Candiracci2.1 Introduction 52.2 Significance 62.3 Stem Cell (SC) Classification 72.4 Stem Cells and Pharmacotoxicological Screenings 82.5 Industrial Utilization Showcases Stem Cell Technology as a Research Tool 82.6 Multipotent Stem Cells (Adult Stem Cells) Characteristics and Current Uses 92.7 Mesenchymal Stem Cells (Adult Stem Cells) 102.8 Hematopoietic Stem Cells (Adult Stem Cells) 112.9 Cardiotoxicity 122.10 Hepatotoxicity 152.11 Epigenetic Profile 172.12 Use of SC and iPSC in Drug Safety 182.13 Conclusions and Future Applications 19Acknowledgments 19References 193 Stem Cells: A Potential Source for High Throughput Screening in Toxicology 26Harish K Handral, Gopu Sriram, and Tong Cao3.1 Introduction 263.2 Stem Cells 273.3 High Throughput Screening (HTS) 313.4 Need for a Stem Cell Approach in High Throughput Toxicity Studies 373.5 Role of Stem Cells in High Throughput Screening for Toxicity Prediction 383.6 Conclusion 40Acknowledgement 41Disclosure Statement 41Author’s Contribution 41References 414 Human Pluripotent Stem Cells for Toxicological Screening 50Lili Du and Dunjin Chen4.1 Introduction 504.2 The Biological Characteristics of hPSCs 514.3 Screening of Embryotoxic Effects using hPSCs 524.4 The Potential of hPSC‐Derived Neural Lineages in Neurotoxicology 554.5 The Potential of hPSC ‐Derived Cardiomyocytes in Cardiotoxicity 604.6 The Potential of hPSC‐Derived Hepatocytes in Hepatotoxicity 624.7 Future Challenges and Perspectives for Embryotoxicity and Developmental Toxicity Studies using hPSCs 65Acknowledgments 66References 675 Effects of Culture Conditions on Maturation of Stem Cell‐Derived Cardiomyocytes 71Deborah K. Hansen, Amy L. Inselman, and Xi Yang5.1 Introduction 715.2 Lengthening Culture Time 755.3 Substrate Stiffness 765.4 Structured Substrates 785.5 Conclusions 82Disclaimer 82References 836 Human Stem Cell‐Derived Cardiomyocyte In Vitro Models for Cardiotoxicity Screening 85Tracy Walker, Kate Harris, Evie Maifoshie, and Khuram Chaudhary6.1 Introduction 856.2 Overview of hPSC‐Derived Cardiomyocytes 886.3 Human PSC‐CM Models for Cardiotoxicity Investigations 906.4 Conclusions and Future Direction 112References 1127 Disease‐Specific Stem Cell Models for Toxicological Screenings and Drug Development 122Matthias Jung, Juliane‐Susanne Jung, Jovita Schiller, and Insa S. Schroeder7.1 Evidence for Stem Cell‐Based Drug Development and Toxicological Screenings in Psychiatric Diseases, Cardiovascular Diseases and Diabetes 1227.2 Disease‐Specific Stem Cell Models for Drug Development in Psychiatric Disorders 1277.3 Stem Cell Models for Cardiotoxicity and Cardiovascular Disorders 1327.4 Stem Cell Models for Toxicological Screenings of EDCs 133References 1358 Three‐Dimensional Culture Systems and Humanized Liver Models Using Hepatic Stem Cells for Enhanced Toxicity Assessment 145Ran‐Ran Zhang, Yun‐Wen Zheng, and Hideki Taniguchi8.1 Introduction 1458.2 Hepatic Cell Lines and Primary Human Hepatocytes 1468.3 Embryonic Stem Cells and Induced Pluripotent Stem‐Cell Derived Hepatocytes 1478.4 Ex Vivo: Three‐Dimensional and Multiple‐Cell Culture System 1488.5 In Vivo: Humanized Liver Models 1498.6 Summary 150Acknowledgments 150References 1509 Utilization of In Vitro Neurotoxicity Models in Pre‐Clinical Toxicity Assessment 155Karin Staflin, Dinah Misner, and Donna Dambach9.1 Introduction 1559.2 Current Models of Drug‐Related Clinical Neuropathies and Effects on Electrophysiological Function 1599.3 Cell Types that Can Potentially Be Used for In Vitro Neurotoxicity Assessment in Drug Development 1629.4 Utility of iPSC Derived Neurons in In Vitro Safety Assessment 1679.5 Summary of Key Points for Consideration in Neurotoxicity Assay Development 1709.6 Concluding Remarks 172References 17210 A Human Stem Cell Model for Creating Placental Syncytiotrophoblast, the Major Cellular Barrier that Limits Fetal Exposure to Xenobiotics 179R. Michael Roberts, Shinichiro Yabe, Ying Yang, and Toshihiko Ezashi10.1 Introduction 17910.2 General Features of Placental Structure 18010.3 The Human Placenta 18010.4 Human Placental Cells in Toxicology Research 18210.5 Placental Trophoblast Derived from hESC 18310.6 Isolation of Syncytial Areas from BAP‐Treated H1 ESC Colonies 18510.7 Developmental Regulation of Genes Encoding Proteins Potentially Involved in Metabolism of Xenobiotics 18510.8 Concluding Remarks 191Acknowledgments 192References 19211 The Effects of Endocrine Disruptors on Mesenchymal Stem Cells 196Marjorie E. Bateman, Amy L. Strong, John McLachlan, Matthew E. Burow, and Bruce A. Bunnell11.1 Mesenchymal Stem Cells 19611.2 Endocrine Disruptors 19811.3 Pesticides 20111.4 Alkyl Phenols and Derivatives 20611.5 Bisphenol A 21111.6 Polychlorinated Biphenyls 21611.7 Phthalates 22111.8 Areas for Future Research 22511.9 Conclusions 226Abbreviations 226References 22812 Epigenetic Landscape in Embryonic Stem Cells 238Xiaonan Sun, Nicholas Spellmon, Joshua Holcomb, Wen Xue, Chunying Li, and Zhe Yang12.1 Introduction 23812.2 DNA Methylation in ESCs 23912.3 Histone Methylation in ESCs 24012.4 Chromatin Remodeling and ESCs Regulation 24112.5 Concluding Remarks 242Acknowledgements 243References 243PART II 24713 The Effect of Human Pluripotent Stem Cell Platforms on Preclinical Drug Development 249Kevin G. Chen13.1 Introduction 24913.2 Core Signaling Pathways Underlying hPSC Stemness and Differentiation 25013.3 Basic Components of In Vitro and Ex Vivo hPSC Platforms 25113.4 Diverse hPSC Culture Platforms for Drug Discovery 25213.5 Representative Analyses of hPSC‐Based Drug Discovery 25513.6 Current Challenges and Future Considerations 25713.7 Concluding Remarks 260Acknowledgments 260References 26014 Generation and Application of 3D Culture Systems in Human Drug Discovery and Medicine 265H. Rashidi and D.C. Hay14.1 Introduction 26514.2 Traditional Scaffold‐Based Tissue Engineering 26614.3 Scaffold‐Free 3D Culture Systems 26914.4 Modular Biofabrication 27014.5 3D Bioprinting 27014.6 Tissue Modelling and Regenerative Medicine Applications of Pluripotent Stem Cells 27214.7 Applications in Drug Discovery and Toxicity 27514.8 Conclusions 278References 27815 Characterization and Therapeutic Uses of Adult Mesenchymal Stem Cells 288Juliann G. Kiang15.1 Introduction 28815.2 MSC Characterization 28915.3 MSCs and Tissue or Organ Therapy 29315.4 Conclusions 298Acknowledgments 298References 29816 Stem Cell Therapeutics for Cardiovascular Diseases 303Yuning Hou, Xiaoqing Guan, Shukkur M. Farooq, Xiaonan Sun, Peijun Wang, Zhe Yang,and Chunying Li16.1 Introduction 30316.2 Types of Stem/Progenitor Cell‐Derived Endothelial Cells 30416.3 EPC and Other Stem/Progenitor Cell Therapy in CVDs 30616.4 Strategies and Approaches for Enhancing EPC Therapy in CVDs 30616.5 Concluding Remarks 315Acknowledgments 316References 31617 Stem‐Cell‐Based Therapies for Vascular Regeneration in Peripheral Artery Diseases 324David M Smadja and Jean‐Sébastien Silvestre17.1 Sources of Stem Cells for Vascular Regeneration 32517.2 Canonic Mechanisms Governing Vascular Stem Cells Therapeutic Potential 32917.3 Stem‐Cell‐Based Therapies in Patients with Peripheral Artery Disease 333References 33718 Gene Modified Stem/Progenitor‐Cell Therapy for Ischemic Stroke 347Yaning Li, Guo‐Yuan Yang, and Yongting Wang18.1 Introduction 34718.2 Gene Modified Stem Cells for Ischemic Stroke 34818.3 Gene Transfer Vectors 35418.4 Unsolved Issues for Gene‐Modified Stem Cells in Ischemic Stroke 35618.5 Conclusion 356Abbreviations 356Acknowledgments 357References 35719 Role of Stem Cells in the Gastrointestinal Tract and in the Development of Cancer 363Pengyu Huang, Bin Li, and Yun‐Wen Zheng19.1 Introduction 36319.2 GI Development and Regeneration 36519.3 GI Tumorigenesis and Stemness Gene Expression 36719.4 Toxicants and Other Stress Trigger Epigenetic Changes, Dedifferentiation, and Carcinogenesis 36819.5 Summary and Perspective 369Acknowledgments 369References 37020 Cancer Stem Cells: Concept, Significance, and Management 375Haseeb Zubair, Shafquat Azim, Sanjeev K. Srivastava, Arun Bhardwaj, Saravanakumar Marimuthu, Mary C. Patton, Seema Singh, and Ajay P. Singh20.1 Introduction 37520.2 Stem Cells and Cancer: Historical Perspective 37620.3 Cancer Stem Cells 37720.4 Identification and Isolation of CSCs 38220.5 Pathological Significance of Cancer Stem Cells 38820.6 Pathways Regulating Cancer Stem Cells 38920.7 Therapeutic Strategies Targeting Cancer Stem Cells 39420.8 Conclusion and Future Directions 399References 40021 Stem Cell Signaling in the Heterogeneous Development of Medulloblastoma 414Joanna Triscott and Sandra E. Dunn21.1 Brain Tumor Cancer Stem Cells 41421.2 Medulloblastoma 41621.3 Hijacking Cerebellar Development 41721.4 Molecular Classification of MB 42021.5 Mouse Models and Cell of Origin 42421.6 Additional Drivers of MB 42521.7 Repurposing Off‐Patent Drugs 42621.8 Emerging Therapies for MB 42821.9 Conclusion 429Acknowledgments 429References 42922 Induced Pluripotent Stem Cell‐Derived Outer-Blood‐Retinal Barrier for Disease Modeling and Drug Discovery 436Jun Jeon, Nathan Hotaling, and Kapil Bharti22.1 Introduction 43622.2 The Outer Blood‐Retinal Barrier 43722.3 iPSC‐Based Model of the Outer-Blood‐Retinal-Barrier 43922.4 iPSC Based OBRB Disease Models 44222.5 Applications of iPSC‐Based Ocular Disease Models for Drug Discovery 44822.6 Conclusion and Future Directions 451References 45123 Important Considerations in the Therapeutic Application of Stem Cells in BoneHealing and Regeneration 458Hoda Elkhenany, Shawn Bourdo, Alexandru Biris, David Anderson, and Madhu Dhar23.1 Introduction 45823.2 Stem Cells, Progenitor Cells, Mesenchymal Stem Cells 45923.3 Scaffolds 46123.4 Animal Models in Bone Healing and Regeneration 46423.5 Conclusions and Future Directions 472References 47224 Stem Cells from Human Dental Tissue for Regenerative Medicine 481Junjun Liu and Shangfeng Liu24.1 Introduction 48124.2 Dental Stem Cells 48224.3 Potential Clinical Applications 48824.4 Safety 49224.5 Dental Stem Cell Banking 49324.6 Conclusions and Perspective 494References 49525 Stem Cells in the Skin 502Hongwei Wang, Zhonglan Su, Shiyu Song, Ting Su, Mengyuan Niu, Yaqi Sun, and Hui Xu25.1 Introduction 50225.2 Stem Cells in the Skin 50325.3 Isolation and the Biological Markers of Skin Stem Cells 50625.4 Skin Stem Cell Niches 50825.5 Signaling Control of Stem Cell Differentiation 51025.6 Stem Cells in Skin Aging 51425.7 Stem Cells in Skin Cancer 51625.8 Medical Applications of Skin Stem Cells 51825.9 Conclusions and Future Directions 520References 521Author Index 527Subject Index 529