Current Topics in iPSCs Technology

Current Topics in iPSCs provides a deep analysis of the underlying fundamentals that support short and mid-term developments and milestones in the business of mesenchymal stem cell therapies. This volume explores the next frontier of MSC therapies and how the transformational potential of therapeutic adult cells will be realised in all therapy areas. The impacts of clinical and economic benefits are dissected throughout each of the chapters. Written by thought leaders in the field for those curious about the interface of science and business.

• Explores the strategy at the forefront of the science of mesenchymal stem cells
• Provides an overview of all therapy areas where MSC and MSC-derived products can be used therapeutically
• Depicts transformational changes in healthcare that enable the implementation of MSC-powered technology platforms

• Language: English
• Publisher: Academic Press
• Release date: Jan 18, 2022
• ISBN: 9780323983983

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Current Topics in iPSCs Technology

Volume 17

Editor

Alexander Birbrair

Federal University of Minas Gerais, Department of Pathology, Belo Horizonte, Minas Gerais, Brazil

Columbia University Medical Center, Department of Radiology, New York, NY, United States

Table of Contents

Cover image

Title page

Advances in Stem Cell Biology

Copyright

Dedication

Contributors

About the editor

Preface

Acknowledgment

Chapter 1. Regulatory and policy considerations in iPSC research

Introduction

Three primary domains

Materials acquisition

iPSC derivation and differentiation

Product and data stewardship

Conclusion

Chapter 2. hiPSCs for population genetics

Introduction

hiPSCs for disease-related genetics and functional genomics

hiPSC for pharmacogenomics

Future directions

Chapter 3. Using human induced pluripotent stem cells to advance personalized/precision medicine

Introduction

hiPSCs in patient-specific genome research

hiPSCs in patient-specific epigenome research

hiPSCs in patient-specific proteomic research

hiPSCs in patient-specific metabolomic research

Example of using hiPSCs to establish a databank for large-scale personalized medicine

Challenges of hiPSC disease modeling

Chapter 4. hiPSC disease modeling with 3D organoids: bioengineering perspective

Introduction

Organoid differentiation and characterization

Applications

Perspective

Conclusions

Chapter 5. The differentiation of embryonic stem cells and induced pluripotent stem cells into airway and alveolar epithelial cells

Introduction

Murine and human lung development

ESC and human IPSC differentiation into airway and alveolar epithelial cells

Conclusion

Chapter 6. Transplantation of human iPSC-derived kidney organoids

Introduction

Metanephric grafts

Limitations of kidney organoids

Implantation into neonatal mice

Formation of glomerulus-like structures

Readouts of glomerular function

Organoids as regenerative therapeutics

Safety concerns

Conclusion

Chapter 7. An update on clinical applications of iPSCs from a genomic point of view

Introduction

Types of genomic aberrations

Origin of genomic aberrations in iPSCs

Effects of mutations on the phenotype of iPSCs

Improved reprogramming methods to reduce genomic instability

Conclusions and future outlook

Chapter 8. Replication-associated DNA damage in induced pluripotent stem cells

Introduction

Genomic instability in PSCs

DNA damage, repair, and response in PSCs

Potential sources of replication-associated DNA damage in PSCs

DNA damage response in PSCs

Commentary: future trends and directions

Chapter 9. Epigenetic modifications in induced pluripotent stem cells to boost myogenic commitment

Epigenetics

Myogenesis

Differentiating iPSCs toward the skeletal muscle lineage

Epigenetic memory

Epigenetics in skeletal muscle differentiation

Epigenetic modifications to improve skeletal muscle differentiation

Future perspectives

Chapter 10. Applications for induced pluripotent stem cells in reproductive medicine

Introduction

Cellular and molecular mechanisms of human germ cell development—a roadmap for the derivation of germ cells from hiPSCs

Potential use of hiPSC-derived gametes—unmet needs in ARTs and research models

Generation of hiPSC-derived germ cells

Patient-specific modeling of gametogenesis using hPGCLCs

iPSC-derived reproductive somatic cells

Challenges and future directions

Chapter 11. iPSCs in insulin resistance, type 2 diabetes, and the metabolic syndrome

Introduction

Insulin resistance, type 2 diabetes, and the metabolic syndrome

iPSC differentiation to relevant metabolic cell types

iPSC-based models for insulin resistance, type 2 diabetes, and the metabolic syndrome

Future directions

Chapter 12. Induced pluripotent stem cells for cystic fibrosis

Introduction

Generalities of iPSCs

Cystic fibrosis

Functional assay for CFTR or assay for measuring CFTR activity (Fig. 12.1)

iPSCs for the respiratory system (Table 12.2)

iPSCs for the gatrointestinal system (Table 12.3)

Concluding remarks and future directions

Declaration of interest

Chapter 13. Exploring 15q13.3 copy number variants in iPSCs

Introduction

More work to be done

Chapter 14. Human induced pluripotent stem cells for modeling Brugada syndrome

Introduction

Long QT syndrome

Catecholaminergic polymorphic ventricular tachycardia

Brugada syndrome

Short QT syndrome

Human induced pluripotent stem cells

Human cardiomyocytes from induced pluripotent stem cells

Brugada syndrome animal models

Heterologous expression systems

Native human cardiomyocytes

Brugada syndrome models using hiPSC-CMs

Limitations of hiPSC-CMs

Chapter 15. iPSCs for erythromycin arrhythmogenicity testing

Introduction

The occurrence of ventricular fibrillation, prognostic difficulties

Experimental modeling approaches: iPSCs

Timeline for arrhythmogenicity testing with a standard obstacle

Developing cellular systems for in vitro studies of erythromycin arrhythmogenicity

Future trends

Chapter 16. Therapeutic potential of induced pluripotent stem cell–derived extracellular vesicles: Quo Vadis? Terra incognito

Introduction

Extracellular vesicle nomenclature and characterization

Extracellular vesicle biogenesis and cargo types

Extracellular vesicle isolation and visualization approaches

Bioengineering and targeting of extracellular vesicles

Therapeutic application of adult stem cell–derived extracellular vesicles

Therapeutic application of pluripotent stem cell–derived extracellular vesicles

The road ahead

Chapter 17. Proteomic approach for creation of the protein marker panels to control the quality of human induced pluripotent stem cells

Introduction

Materials and methods

Results

Discussion

Conclusions

Chapter 18. Application of induced pluripotent stem cells in tissue engineering

Introduction

Stem cells

Different ways of scaffolds fabrication

Electrospinning

3D printing

Biomaterials

Natural biomaterials

Synthetic biomaterials

iPSC applications in tissue engineering

Conclusion and iPSCs perspective in tissue engineering

Chapter 19. Induced pluripotent stem cell–derived extracellular vesicles in regenerative medicine

Introduction

Classification and biogenesis of EVs

Therapeutic potential of exosomes in cardiovascular disease

Therapeutic potential of microvesicles in cardiovascular disease

Current clinical perspective: challenges and promises of extracellular vesicles

Conclusion

Chapter 20. iPSCs and toxicology: predictive tool for present and future

Introduction: iPSCs in human toxicology

iPSCs in species-specific toxicology

Conclusions and future perspectives

Chapter 21. Rejuvenation through iPSCs and reprogramming in vivo and in vitro

What is aging?

Is aging universal? Is aging reversible or irreversible?

Mammalian/vertebrate aging

Can aging in complex adult organisms relevant to humans such as vertebrates that have reached sexual maturity be rejuvenated?

Rejuvenation by iPSC induction in vivo: first attempts by complete reprogramming

Rejuvenation by iPSC induction in vivo: partial reprogramming is successful

Rejuvenation by iPSC induction: follow-ups

Partial OSKM induction: kinetics of resetting DNAm age

Partial reprogramming of iPSCs: the future

Index

Advances in Stem Cell Biology

Series Editor

Alexander Birbrair

Copyright

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This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

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A catalogue record for this book is available from the British Library

ISBN: 978-0-323-99892-5

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Cover Designer: Mark Rogers

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Dedication

This book is dedicated to my mother, Marina Sobolevsky, of blessed memory, who passed away during the creation of this volume. Professor of Mathematics at the State University of Ceará (UECE), she was loved by her colleagues and students, whom she inspired by her unique manner of teaching. All success in my career and personal life I owe to her.

My father, Lev Birbrair, and my beloved mom, Marina Sobolevsky, of blessed memory (July 28, 1959–June 3, 2020)

Contributors

K.I. Agladze

Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia

M. F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow, Russia

Ibrahim Akin

First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany

DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Germany

Michail A. Alterman

Tumor Vaccine and Biotechnology Branch, Division of Cellular and Gene Therapies, FDA, Center for Biologics Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, MD, United States

Center for Drugs Evaluation and Research, FDA, Silver Spring, MD, United States

Abdolreza Ardeshirylajimi

Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Tehran Province, Iran

SinaCell Research and Product Center, Tehran, Tehran Province, Iran

Alessia Bertero,     Università degli Studi di Milano, Department of Environmental Science and Policy (ESP), Milan, Italy

Rahulkumar Bhoi,     Department of Biomedical Engineering, University of North Texas, Denton, TX, United States

Natacha Breuls,     Translational Cardiomyology, Department of Development and Regeneration, Leuven, Belgium

Anne Bush

Center for Stem Cells & Regenerative Medicine, Sanford Burnham Prebys Medical Discovery Institute (SB), La Jolla, CA, United States

Sanford Consortium for Regenerative Medicine (SCRM), La Jolla, CA, United States

Francesca Caloni,     Università degli Studi di Milano, Department of Environmental Science and Policy (ESP), Milan, Italy

Ivan Carcamo-Orive,     Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Institute and Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, United States

Zhifen Chen

Harvard Stem Cell Institute, Harvard University, Cambridge, MA, United States

Cardiology Department, German Heart Centre Munich, Munich, Germany

Technical University of Munich, Munich, Germany

Teresa Coccini,     Istituti Clinici Scientifici Maugeri IRCCS, Laboratory of Clinical and Experimental Toxicology, Toxicology Unit, Pavia, Italy

Massimo Conese,     Department of Medical and Surgical Science, University of Foggia, Foggia, Italy

Chad A. Cowan,     Harvard Stem Cell Institute, Harvard University, Cambridge, MA, United States

Nathan James Cunningham,     Cardiovascular Institute, Stanford University, Stanford, CA, United States

Ibrahim El-Battrawy

First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany

DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Germany

Benjamin S. Freedman,     Division of Nephrology, Kidney Research Institute, Institute for Stem Cell and Regenerative Medicine, Departments of Medicine, Pathology (Adjunct), Bioengineering (Adjunct), University of Washington School of Medicine, Seattle, WA, United States

Andrée Gauthier-Fisher,     CReATe Fertility Centre, Toronto, ON, Canada

Melkamu Getie-Kebtie

Tumor Vaccine and Biotechnology Branch, Division of Cellular and Gene Therapies, FDA, Center for Biologics Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, MD, United States

Center for Drugs Evaluation and Research, FDA, Silver Spring, MD, United States

Nefele Giarratana

Translational Cardiomyology, Department of Development and Regeneration, Leuven, Belgium

Stem Cell Laboratory, Department of Pathophysiology and Transplantation, University of Milan, Unit of Neurology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Milan, Italy

Madelyn A. Gillentine,     Seattle Children's Hospital, Seattle, WA, United States

Christopher Grunseich,     Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States

Mirabelle S.H. Ho,     CReATe Fertility Centre, Toronto, ON, Canada

Miriel S.H. Ho,     CReATe Fertility Centre, Toronto, ON, Canada

Deborah A. Hursh,     Division of Cell and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States

Gentaro Ikeda,     Department of Medicine (Cardiovascular Medicine) and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

Ji Hye Jung,     Department of Medicine (Cardiovascular Medicine) and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

Martin H. Kang,     Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute (OHRI), University of Ottawa, Ottawa, ON, Canada

Yong Kyun Kim

Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea

Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea

Jacqueline Kowitz,     First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany

Siegfried Lang

First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany

DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Germany

Onofrio Laselva

Programme in Molecular Medicine, Hospital for Sick Children, Toronto, ON, Canada

Department of Physiology, University of Toronto, Toronto, ON, Canada

Department of Medical and Surgical Science, University of Foggia, Foggia, Italy

Jennifer Lei,     Regenerative Sciences Institute, Sunnyvale, CA, United States

Sandra L. Leibel

Department of Pediatrics, School of Medicine, University of California-San Diego (UCSD), La Jolla, CA, United States

Center for Stem Cells & Regenerative Medicine, Sanford Burnham Prebys Medical Discovery Institute (SB), La Jolla, CA, United States

Sanford Consortium for Regenerative Medicine (SCRM), La Jolla, CA, United States

Clifford L. Librach

CReATe Fertility Centre, Toronto, ON, Canada

Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada

Department of Physiology, University of Toronto, Toronto, ON, Canada

Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada

Geoffrey P. Lomax,     California Institute for Regenerative Medicine (CIRM), Oakland, CA United States

Maryam Mahmoodinia Maymand,     Stem Cell and Regenerative Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering & Biotechnology (NIGEB), Tehran, Tehran Province, Iran

Rachael N. McVicar

Center for Stem Cells & Regenerative Medicine, Sanford Burnham Prebys Medical Discovery Institute (SB), La Jolla, CA, United States

Sanford Consortium for Regenerative Medicine (SCRM), La Jolla, CA, United States

Andrew R. Mendelsohn,     Regenerative Sciences Institute, Sunnyvale, CA, United States

Anna R. Mendelsohn

Regenerative Sciences Institute, Sunnyvale, CA, United States

University of California San Diego, La Jolla, CA, United States

Sadegh lotfalah Moradi,     Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Tehran Province, Iran

Yasuhiro Murakawa

RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan

IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy

Dan Nir,     CReATe Fertility Centre, Toronto, ON, Canada

Connor G. O'Brien,     Department of Medicine (Cardiovascular Medicine) and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

A.D. Podgurskaya

Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia

M. F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow, Russia

Natalia S. Pripuzova

Tumor Vaccine and Biotechnology Branch, Division of Cellular and Gene Therapies, FDA, Center for Biologics Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, MD, United States

NPDK Bioconsulting LLC, San Diego, CA, United States

Maurilio Sampaolesi

Translational Cardiomyology, Department of Development and Regeneration, Leuven, Belgium

Histology and Medical Embryology Unit, Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Sapienza University of Rome, Italy

M.M. Slotvitsky

Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia

M. F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow, Russia

Evan Y. Snyder

Department of Pediatrics, School of Medicine, University of California-San Diego (UCSD), La Jolla, CA, United States

Center for Stem Cells & Regenerative Medicine, Sanford Burnham Prebys Medical Discovery Institute (SB), La Jolla, CA, United States

Sanford Consortium for Regenerative Medicine (SCRM), La Jolla, CA, United States

Shi Su,     Cardiovascular Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Colin Sweeney,     Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States

Bernard Thébaud,     Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute (OHRI), University of Ottawa, Ottawa, ON, Canada

V.A. Tsvelaya

Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia

M. F. Vladimirsky Moscow Regional Research Clinical Institute, Moscow, Russia

Haritha Vallabhaneni,     Division of Cell and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States

Evgeniya A. Vaskova,     Department of Medicine (Cardiovascular Medicine) and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

Huaxiao Yang,     Department of Biomedical Engineering, University of North Texas, Denton, TX, United States

Phillip C. Yang,     Department of Medicine (Cardiovascular Medicine) and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

Laura Yedigaryan,     Translational Cardiomyology, Department of Development and Regeneration, Leuven, Belgium

Masahito Yoshihara,     Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

Xiaobo Zhou

First Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany

DZHK (German Center for Cardiovascular Research), Partner Site, Heidelberg-Mannheim, Germany

Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological, Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China

About the editor

Alexander Birbrair

Dr. Alexander Birbrair received his bachelor's biomedical degree from Santa Cruz State University in Brazil. He completed his PhD in Neuroscience, in the field of stem cell biology, at the Wake Forest School of Medicine under the mentorship of Osvaldo Delbono. Then, he joined as a postdoc in stem cell biology at Paul Frenette's laboratory at Albert Einstein School of Medicine in New York. In 2016, he was appointed faculty at Federal University of Minas Gerais in Brazil, where he started his own lab. His laboratory is interested in understanding how the cellular components of different tissues function and control disease progression. His group explores the roles of specific cell populations in the tissue microenvironment by using state-of-the-art techniques. His research is funded by the Serrapilheira Institute, CNPq, CAPES, and FAPEMIG. In 2018, Alexander was elected affiliate member of the Brazilian Academy of Sciences, in 2019, he was elected member of the Global Young Academy (GYA), and in 2021 he was elected affiliate member of The World Academy of Sciences (TWAS). He is the Founding Editor and Editor-in-Chief of Current Tissue Microenvironment Reports, and Associate Editor of Molecular Biotechnology. Alexander also serves in the editorial board of several other international journals: Stem Cell Reviews and Reports, Stem Cell Research, Stem Cells and Development, and Histology and Histopathology.

Preface

This book's initial title was iPSCs: Recent Advances. Nevertheless, because of the ongoing strong interest in this theme, we were able to collect more chapters than would fit in one single volume, covering induced pluripotent stem cells (iPSCs) biology from different perspectives. Therefore, the book was subdivided into several volumes.

This volume Current Topics in iPSC Technology offers contributions by known scientists and clinicians in the multidisciplinary areas of biological and medical research. The chapters bring up-to-date comprehensive overviews of current advances in the field. This book describes recent advances in the use of iPSCs to model several diseases in vitro, enabling us to study the cellular and molecular mechanisms involved in different pathologies. Further insights into these mechanisms will have important implications for our understanding of disease appearance, development, and progression. The authors focus on the modern state-of-the-art methodologies and the leading-edge concepts in the field of stem cell biology. In recent years, remarkable progress has been made in the obtention of iPSCs and their differentiation into several cell types, tissues, and organs using state-of-the-art techniques. These advantages facilitated identification of key targets and definition of the molecular basis of several disorders. Thus, this book is an attempt to describe the most recent developments in the area of iPSCs technology, which is one of the rising hot topics in the field of molecular and cellular biology today. Here, we present a selected collection of detailed chapters on what we know so far about iPSC technology. Twenty-one chapters written by experts in the field summarize the present knowledge about iPSC technology.

Geoffrey P Lomax from California Institute for Regenerative Medicine discusses regulatory and policy considerations in iPSC research. Chad A. Cowan and colleagues from Harvard University update us with what we know about iPSCs for population genetics. Evan Y. Snyder and colleagues from University of California-San Diego compile our understanding of using human iPSCs to advance personalized/precision medicine. Nathan James Cunningham and Huaxiao Yang from Stanford University give a bioengineering perspective on hiPSC disease modeling with 3D organoids. Martin H Kang and Bernard Thébaud from Ottawa Hospital Research Institute introduce what we know so far about the differentiation of iPSCs into airway and alveolar epithelial cells. Yong Kyun Kim and Benjamin S. Freedman from University of Washington School of Medicine describe transplantation of iPSC-derived human kidney organoids. Masahito Yoshihara and Yasuhiro Murakawa from RIKEN Center for Integrative Medical Sciences give an update on clinical applications of iPSCs from a genomic point of view. Haritha Vallabhaneni and Deborah A. Hursh from Food and Drug Administration address the importance of DNA damage and replication in iPSCs. Maurilio Sampaolesi and colleagues from KU Leuven explain epigenetic modifications in iPSCs to boost myogenic commitment. Andrée Gauthier-Fisher and colleagues from University of Toronto debate the importance of iPSCs in reproductive medicine. Ivan Carcamo-Orive from Stanford University School of Medicine talks about iPSCs in insulin resistance, type 2 diabetes, and the metabolic syndrome. Onofrio Laselva and Massimo Conese from University of Foggia consider iPSCs for cystic fibrosis. Madelyn A. Gillentine from University of Washington focuses on exploring 15q13.3 copy number variants in iPSCs. Ibrahim El-Battrawy and colleagues from University Medical Centre Mannheim give an overview of iPSCs for modeling Brugada syndrome. K.I. Agladze and colleagues from Moscow Institute of Physics and Technology present iPSCs for erythromycin arrhythmogenicity testing. Mirabelle S. H. Ho and colleagues from The CReATe Fertility Centre highlight the therapeutic potential of iPSC-derived extracellular vesicles. Natalia S. Pripuzova and colleagues from US Food and Drug Administration introduce a proteomic approach for the creation of protein marker panels to control for quality of human iPSCs. Abdolreza Ardeshirylajimi and colleagues from Shahid Beheshti University of Medical Sciences expose the application of iPSCs in tissue engineering. Phillip C. Yang and colleagues from Stanford University School of Medicine outline the application of iPSC-derived secretome in regenerative medicine. Francesca Caloni and colleagues from Università degli Studi di Milano debate iPSCs as predictive tool for present and future in toxicology. Finally, Andrew Mendelsohn from Regenerative Sciences Institute discusses rejuvenation through iPSCs.

It is hoped that the chapters published in this book will become a source of reference and inspiration for future research ideas. I would like to express my deep gratitude to my wife, Veranika Ushakova, and Ms. Billie Jean Fernandez and Ms. Elisabeth Brown from Elsevier, who helped at every step of the execution of this project.

Alexander Birbrair

Editor

Acknowledgment

The cover was kindly provided by Miriel Ho.

Chapter 1: Regulatory and policy considerations in iPSC research

Geoffrey P. Lomax     California Institute for Regenerative Medicine (CIRM), Oakland, CA United States

Abstract

Enthusiasm for scientific discovery involving the derivation of induced pluripotent stem cells (iPSCs) may cause researchers to overlook regulatory and policy considerations particularly in early-stage discovery research. However, as the global regulatory policy landscape becomes more complex, researchers should strive to ensure their protocols conform to foreseeable international standards. Programs that are not aligned with this policy landscape may encounter regulatory bottlenecks as they advance—particularly preclinical research. In the context of iPSC research, there are a set of regulatory norms that should guide basic and clinical programs. These norms are applicable into three general areas—(1) materials (biospecimen) acquisition, (2) iPSC derivation and differentiation, and (3) product (cell line) and data stewardship. This chapter draws on experience with the administration of research grant awards and investment opportunities to suggest strategies for anticipating and addressing regulatory policy considerations in early-stage research programs.

Keywords

EMA; Ethics; FDA; Guidelines; Human subjects; Informed consent; Institutional review board (IRB); Oversight; Policy; Regulation; Research donor

Introduction

Three primary domains

Materials acquisition

Donor and sample screening for infectious agents

Payments to biospecimen donors

Sensitive use of specimens

Return of results

iPSC derivation and differentiation

Product and data stewardship

Future uses

Distribution and transfer agreements

Commercial use

Genomic characterization and data sharing

Organizational excellence

Conclusion

References

Introduction

Since 2006, when the first induced pluripotent stem cell (iPSC) lines were derived, the California Institute for Regenerative Medicine (CIRM) has been one of the leading funding organizations for pluripotent stem cell research. As of 2020, the institute had funded 123 awards involving iPSC generation (California Institute for Regenerative Medicine, 2020a, 2020b ). In 2012, CIRM partnered with Cellular Dynamics International (now known as FUJIFILM Cellular Dynamics, Inc.) to develop the world's largest iPSC bank (Lin et al., 2020). In addition, CIRM has collaborated with international organizations to support the development of quality control standards and guidelines with the aim of advancing the use of iPSC-derived products to address unmet medical needs (Abbot et al., 2018). Collectively, these programs represent an investment of over USD 285 million. The process of evaluating, awarding, and administering iPSC programs has provided the CIRM team with a first-hand perspective of the legal, regulatory, and policy considerations that arise in iPSC research.

CIRM has observed that both basic and clinical research programs can encounter regulatory policy bottlenecks. Issues may be related to iPSC line selection, human subject protocols (e.g., informed consent), or administrative gaps (e.g., lack of documentation), among others. In addition, CIRM continually seeks to build strategic partnerships within its portfolio programs. A major focus of the partnership program is attracting investments from private industry, USD 1.64 billion as of 2019 (California Institute, 2018, 2020). As part of the due-diligence process, investors are attentive to regulatory considerations that could impact the commercial viability of cell or cell-based products. Thus, there are a consistent set of considerations that arise in partnering discussions regarding the provenance and stewardship of cell lines.

This chapter draws on CIRM's experience with the administration of research awards and the evaluation of investment opportunities, to describe regulatory policy considerations related to iPSC research that can impact basic and clinical development programs and their subsequent partnering with commercial entities. The aim is to provide a framework to segment the various policy domains along the product development continuum. For each domain, strategies are suggested for navigating the regulatory and policy landscape to ensure that cell lines selection or iPSC derivation protocols are fit-for-purpose. The objective is to identify steps that can be taken to ensure research programs are on a robust regulatory footing.

The reader should note that this chapter offers generalized recommendations (not legal consultation) to address common regulatory policy considerations. As suggested in the Organizational Excellence section, the optimal approach requires close collaboration between researchers and regulatory policy specialists. A priori collaboration serves to identify and anticipate considerations applicable to defined research protocols in specified regulatory policy jurisdictions.

Three primary domains

The proposed framework includes three primary domains for segmenting regulatory and policy considerations—(1) materials acquisition, (2) iPSC derivation and differentiation, and (3) product and data stewardship (Fig. 1.1). This simplified framework is applicable independent of cell line grade (e.g., research vs. clinical) and source (e.g., new derivation from a somatic cell biospecimen vs. banked iPSC lines).

Successfully navigating these domains may be conceptualized as a reverse engineering exercise where one considers the long-term aims of the research program and strives to ensure all feedstocks and processes are compliant with regulatory policy requirements associated with these outcomes. The central principle is compatibility. For example, if a preclinical program's aim is to develop iPSC-derived neurons for human transplantation, then one should consider the regulatory policy requirements that will govern the final product. In this example, there are specific materials acquisition considerations, such as donor screening, that must be accounted for if the final product is to be suitable for human transplantation. In addition, advanced consideration should be given to information needs such as genomic characterization. As will be discussed later in this chapter, emerging requirements for data management and stewardship are best satisfied through prospective planning, systematic documentation, and robust informed consent.

Figure 1.1 Domains for segmenting regulatory and policy considerations.

This chapter will focus primarily on materials acquisition and product and data stewardship. Acquisition and stewardship are inextricably linked through regulatory policy requirements satisfied by the implementation of administrative procedures relating to consent, oversight, and verification/certification. In addition, there is some variation internationally in acquisition and stewardship requirements and/or how compliance is evaluated (Caulfield et al., 2009). Therefore, recommendations will focus on steps designed to make iPSCs optimally compliant for international use. Specific technical criteria pertaining to reagent selection, documentation, and testing in the process of iPSC derivation are not emphasized. Such requirements are well described in regulatory guidance documents and related publications (Pamies et al., 2017; Abranches et al., 2020).

For many of the considerations highlighted in this chapter, specific examples of how related issues were resolved in the context of CIRM programs are provided. The aim of providing these examples is to offer the reader clarity and benchmarks for how they might address similar or related issues. However, for some issues, particularly those of a contentious ethical nature, differing norms, social values, institutional policies, or legal frameworks may necessitate different outcomes. Therefore, while the issues described are applicable to iPSC research in general, researchers should strive to engage their institutional ethics boards, legal councils, and regulatory officials to ensure appropriate protocol design.

Materials acquisition

One factor contributing to either the delay or inability to partner an iPSC research program is the selection of biospecimens by convenience rather than obtaining appropriately vetted samples. This situation arises, in part, because of historic policies that allow nonidentifiable biospecimens (medical waste) to be routinely collected and used in research (United States Department of Health and Human Services, 2008). Such use is generally appropriate for certain research and training activities, particularly those that result in the destruction of the sample. However, these specimens are not good candidates for preclinical research or cell banking protocols. Excitement over reports of human iPSC generation had led some laboratories to utilize routinely banked biospecimens and cell lines or medical discards for early experiments. Often such use was benign due to high derivation failure rates, but in some instances, resulting iPSC lines became foundational tools for research programs. Table 1.1 provides a generalizable schema.

Table 1.1

Use of nonidentifiable biospecimens to derive iPSC lines raises unique ethical concerns. These concerns emanate from the fact (1) donor cells are transformed, (2) the resulting iPSCs undergo self-renewal (e.g., may be immortalized), and (3) have the potential to differentiate into any cell in the body (Lomax and Aungst, 2017). Disquiet over the immortalization of cell lines without complete donor consent has been the subject of ongoing social controversy (Skloot, 2010). Further, extensive genomic characterization of iPSC lines also creates concern over the possibility of reidentification. Guidelines in the United States regarding the use of nonidentifiable specimens were revised in 2008 in part over worries that specimens could be reidentified through genomic analysis (United States Department of Health and Human Services, 2008). Finally, the provenance of lines used in stem cell research, in general, became an increasingly sensitive issue with publication of findings indicating deficiencies with consent forms associated with NIH-approved embryonic stem cell lines (Streiffer, 2008). Thus, during the period when iPSC derivation and use was reaching a zenith, expectations for donor consent and documentation of materials provenance increased substantially (Institute of Medicine and National Research Council, 2010).

Given this milieu of ethics policy concerns, there is general consensus that iPSC derivation protocols should utilize newly obtained biospecimens or specimens from research banks where donors have provided robust consent consistent with iPSC derivation and use. New biospecimen collection may be optimal because the consent process can be tailored to specific research protocols and include the unique considerations associated with pluripotent stem cells (Institute of Medicine and National Research Council, 2010; International Society for Stem Cell Research, 2016). However, there are also well-developed banking programs containing biospecimens obtained from longitudinal cohorts that may be suitable for iPSC derivation and use (H3 Africa, 2020; UK Biobank, 2019; Lomax et al., 2015). One consideration with longitudinal research cohorts is whether donor recontact and reconsent is required to consent for the proposed use of their specimen. Researchers may want to balance the time and cost associated with recontact and reconsent with de novo derivation from newly collected biospecimens.

Table 1.2, Relevant Disclosures for iPSC Consent, identifies issues typically addressed in the context of iPSC derivation. The list is not exhaustive, but it does aim to capture disclosures that are routinely provided in the context of research protocols with the aim of health and disease modeling and drug discovery. Further, when incorporating disclosures into a consent protocol, care should be given to not imply that all possible uses of the resulting cell lines have been described. Rather, protocols should aim to characterize generalizable categories of use typical to the domain of research. The issues of generalizability and specificity are discussed further in section Future Uses. In addition, sample language is provided to suggest ways to disclose the issue to donors. Finally, conceptual and practical considerations are offered for further consideration.

In the case of the CIRM iPSC Repository, newly obtained blood or skin samples were collected by seven different research programs. Each program provided biospecimens for a standardized derivation protocol performed at a single site. CIRM worked with each of the seven programs to deploy a model consent template specific to the aims of the repository program (California Institute for Regenerative Medicine, 2020a, 2020b ). The template addressed considerations identified in Table 1.2, related to the collection, processing, and distribution of biospecimens, including research aims, risks to the donor, and potential uses of derived lines. A major advantage of de novo collections, as opposed to using banked specimens, is the ability to provide this level of specificity in the consent process. Many of the specific disclosures in the consent template, such as risk associated with participation and research aims, are required in research generally (World Medical Association, 2018). A comprehensive review of consent frameworks for research is beyond the scope of this chapter. However, there are certain disclosures that are particularly relevant and should be applied in iPSC derivation and use protocols.

Table 1.2

Donor and sample screening for infectious agents

There are certain contexts when donors and/or specimens are screened to make an eligibility determination. As alluded to previously, any preclinical development program should utilize cell lines derived from specimens determined to be donor eligible for human transplantation. For example, the US FDA has developed donor eligibility guidance for biospecimens intended for use in cell- or tissue-based products (United States Department of Health and Human Services, 2007). Substantially similar screening requirements exist in many international jurisdictions (Andrews et al., 2015). The qualification of raw materials is the starting point for development programs aiming for cGMP compliance (Abranches et al., 2020). The FDA usually requires that critical preclinical studies be performed on the final product, manufactured using the appropriate cGMP‐qualified process (Carpenter and Rao, 2015). CIRM has observed development programs where the sponsor's initial line was not determined to meet donor eligibility requirements. The program attempted to substitute or derive a new cell line to conform with donor eligibility requirements. However, the data obtained from experiments utilizing the original cell line could not be carried over to research program with the substitute line. The sponsor then attempted, at considerable cost, to replicate results with the replacement product. Often results were not reproducible, and the development program was setback.

Even in the case of research grade lines, there may be instances where infectious disease screening of biospecimens is deemed desirable (Shioda et al., 2018). For example, most blood samples provided to the CIRM iPSC Repository were screened for HIV, HBV, and HCV (Fuji Film, 2020). If infectious disease testing is contemplated on the primary biospecimen, then it must be disclosed in the donor informed consent, and ethics board approved protocols must be in place. Ethics board approval is necessary because donors must be notified in the event of a positive test result. Note this notification requirement is generally limited to blood specimens. Future, downstream, testing of derived cell lines for adventitious agents is routinely conducted as part of quality control protocols, and does not raise the consent and notification issues associated with primary specimens (Charles River, 2020).

Payments to biospecimen donors

Offering payments to individuals for participation in research is a subject of ongoing ethical debate. A fundamental concern is that payments coerce and/or unduly induce individuals to participate in a study (Largent & Fernandez Lynch). International guidelines suggest individuals should be reasonably compensated for … time spent participating in research (van Delden and van der Graaf, 2017). In addition, many protocols allow the reimbursement for costs incurred as a result of research participation. Such costs might include transportation-related expenses. The issue of payments and reimbursement becomes more complex when one considers some jurisdictions may mandate compensation to participants while others may have strict prohibitions (Nyangulu et al., 2019).

CIRM has frequent interactions with commercial entities interested in utilizing lines from the CIRM iPSC Repository. Commercial entities indicated that absence of any payments or reimbursements associated with the CIRM lines was an important consideration for choosing to use the CIRM lines. These users cited variability in international policy as a concern that was best alleviated by using materials for which there were no payments whatsoever. Therefore, in order to create optimal commercial potential, researchers should select existing lines or develop biospecimen collection protocols for new derivations where no payments or reimbursements are made to donors.

As a corollary to not providing payments and reimbursements for the donation of biospecimens, participants should also be informed that their materials may have commercial potential, and they will not own or have a monetary interest in the resulting products. Further, in clinical research, donors may not place restrictions of who may be treated with any resulting medical product.

Sensitive use of specimens

The capacity to differentiate stem cells in vitro has led to the development of model organ (organoid) systems for disease modeling, drug screening, host–microbe interaction, and therapy development (Dutta et al., 2017). The development of brain organoids has emerged as a particularly sensitive concern (Farahany et al., 2018). Further, there may be a future role for personalized organoid development from iPSCs in the diagnosis and treatment of patients with neurological impairments (Miller et al., 2005). For this chapter, numerous individuals involved in the review and oversight of brain organoid research were consulted for guidance in informed consent. Key informants suggested there were challenges in accurately describing the capacity of organoids in relation to the human brain. In other words, there is consensus that existing organoid models did not have capacities such as self-awareness, but simply using the term brain could be suggestive of this capacity and unsettling to donors. At the time of this writing, there was not broad consensus, but Table 1.1 provides suggested language that aligns with the views of those consulted.

Some conditions, such as reproductive disorders and neurological conditions (e.g., autism), are thought to result from sequela associated with early embryogenesis (Miller et al., 2005). Thus, there have been efforts to develop embryo-like structures using colonies of human pluripotent stem cells. Similarly, human gametes may be derived from iPSCs followed by attempts to create embryo-like structures to model disease (Mathews et al., 2009). Given social sensitivity to embryo research, research should verify such uses are consistent with the consent process. As a practical matter, protocols with the aim of using iPSCs to create gametes to study embryogenesis or early development should consent specifically for this aim. Such use may be prohibited by general research banks.

In the case of the CIRM iPSC bank, donors were given the option of opting out of gamete research. Parents and guardians consenting on behalf of minors were most likely to opt out. Ultimately, the material transfer agreement (MTA) from the bank stipulated that materials not be used to directly or indirectly make any human gamete or gamete precursor cell (FUJIFILM Cellular Dynamics Inc., 2018).

Return of results

Studies suggest there is a desire among participants and society to access the results of research, particularly when studies are supported by public funding (Mester et al., 2015). There is broad consensus regarding the social and scientific value of disseminating generalizable findings in research (Open Science by Design, 2018). When recruiting and consenting participants for iPSC research, it is important to distinguish between reporting generalizable results and clinically actionable ones. Despite their best efforts, investigators have indicated that in some limited cases a therapeutic misconception may persist in iPSC research (Cyranoski, September 11, 2019). Such misconceptions include the belief that the resulting cells will inform the treatment of their disease (akin to a personalized medicine tool) and/or the resulting cell lines will be utilized as a therapeutic. This misconception may be particularly acute in populations with cognitive impairment. Investigators may consider engaging caregivers, partners, or other family members in the consent process (where appropriate).

At this time, donors should be informed that the derivation and use of iPSC lines will not provide them with direct medical benefit—notwithstanding the limited number of clinical trial protocols where iPSC lines are derived for therapeutic use. It should be made clear that no personalized medical information will be provided. iPSCs are not sufficiently predictive for clinical purposes for the following reasons:

• Genetic Instability: iPSCs have shown significant genetic variability when reprogrammed and cultured. Therefore, the resulting genotype does not necessarily reflect the donor genotype.

• Validation Criteria: Protocols do not exist to harmonize results from research laboratories using iPSCs with those of Clinical Laboratory Improvement Amendments (CLIA) laboratories.

• Etiologic Complexity: Genetically complex conditions result from a poorly understood confluence of pleiotropic gene effects. Methodologies for the quantification of risk and penetrance have generally not been sufficiently validated.

iPSC derivation and differentiation

As suggested previously, many of the regulatory policy considerations associated with derivation and differentiation are well described in regulatory guidance documents and related publications. However, one aspect of line derivation protocol that should be aligned with the donor informed consent is the ability of specimen donors to withdraw from research. The right to withdraw from research is considered an inalienable human right. However, research conducted on human subjects themselves differs in important respects from research on biological samples. It is therefore not obvious that the same rights should be granted to research participants in the two cases (Helgesson and Johnsson, 2005).

Further, from the standpoint of donor withdrawal, derivative iPSC lines may be viewed as distinct from donated skin and blood specimens. iPSC lines result from the agency of the investigator and involve a transformation of the native material. In addition, derivation requires a commitment of resources. Therefore, it is reasonable to assert that derived cell lines may not be subject to withdrawal in the same manner that individuals or native biospecimens would be. In the case of the CIRM Repository, donors were informed that any residual biospecimens may be withdrawn from research and/or the resulting cell lines could have all links to the donor removed, but the lines themselves would remain in the bank. The point here is not to suggest this is the best policy in every circumstance. Rather, there needs to be a clearly articulated policy for withdrawal from research with clearly defined cut points. Again, in the case of the CIRM Repository, lines could not be withdrawn when at least one clone at passage 5 has been transferred to the repository. Investigators should develop clearly defined cut points in consultation with their institutional ethics board to ensure policy alignment.

Product and data stewardship

Future uses

One of the great challenges of the consent process is the interaction between specificity and the don't know what we don't know problem where future research methods are prohibited because they were not explicitly disclosed. As suggested by Table 1.1, there are numerous specific, yet generalizable, disclosures that describe common uses of cell lines. These examples are intended, in part, to enable the donor to reflect on whether the proposed uses align with their values and beliefs. The value of specificity is that it provides clarity. Such clarity is important, especially when the specific aims of the research are known. However, there have been instances where clear and precise consent forms have subsequently been determined to restrict future research uses (Wadman, 2009). A majority of basic science investment is provided by public and philanthropic sources (Mervis, 2017). Restrictions on future uses are generally detrimental as they prevent science and society from leveraging research investments. Every effort should be made to balance specificity with generalizability to avoid the don't know what we don't know problem. Well-developed research and/or banking protocols should be able to accomplish both. To achieve this balance, consider the following:

• Provide a sufficiently broad statement of intent that accurately demarcates activities to the particular research domain. For example, research grade iPSC lines are intended for the study of health and disease and treatment development.

• When specific activities are described, such as those identified in Table 1.1, present them as examples of how cell lines will be used. Indicate there may be unknown future uses.

• Provide a procedural mechanism for unforeseen future uses. For example, have a process where an ethics committee or oversight body reviews statements of research intent to make an explicit determination that such use is consistent with the original intent.

• Avoid using donor recontact as a means of reconsenting for new uses. One exception would be longitudinal cohort studies where donors are actively collaborating with researchers.

Distribution and transfer agreements

In the event iPSC lines are distributed to third parties, transfer agreements serve to describe contractual obligations related to exchange of materials and data. The MTA should be consistent with the terms of any informed consent and authorization (Heffernan et al., 2017). In this capacity the MTA should serve as a legal instrument to ensure the rights of somatic cell donors are upheld. For example, any restrictions on use of iPSC lines should be delineated in the MTA. Fundamentally, MTAs should serve to enable scientific discovery while ensuring compliance with laws and policies governing research. Some have suggested that MTAs have become overly complex and hinder the exchange of research materials (Bubela et al., 2015). Such complexity is often attributed to concerns over intellectual property and commercialization rights. Controversy surrounding MTAs and intellectual property is noted here for the reference. In the context, of this chapter the MTA should be thought of as a tool for supporting the integrity of the informed consent process.

Commercial use

iPSC collections have become widely used in commercial product development. Given the substantial investment required to market new research and medical products, users of iPSCs for commercial applications are particularly attentive to consent language disclosing the potential for such development. Donors should be informed of the potential for commercial use, as some may object, and further, that they will not have any financial interest in any resulting products from development programs where iPSC lines derived from their biospecimens were utilized (Beskow and Dean, 2008). Such disclosure is an accepted standard of practice in stem cell research, and studies suggest donors are comfortable with specimens contributing to commercial opportunities (Lo and Parham, 2009).

Genomic characterization and data sharing

Genomic and bioinformatics analysis are fundamental tools for stem cell research. In 2014, the CIRM invested $40 million to establish the Center of Excellence in Stem Cell Genomics (CESCG) (Center for Excellence, 2020). The CESCG generates and banks data derived from iPSC lines with the aim of making genomics capabilities available to the entire regenerative medicine community. Genomic platforms are critical tools for systematically characterizing cell differentiation, disease mechanisms and states, and human biology generally. The platforms derive their effectiveness from the capacity to share and analyze large quantities of genomic information associated with specific cell lines. The generation and exchange of such data are generally regulated by laws which establish standards intended to protect individual privacy (European Union, 2018). Pursuant to these laws there are general standards for data stewardship that typically involve controls of data exchange (Knoppers, 2014).

Administrators of genomic data sharing platforms are increasingly obligated to ensure the end uses of data are consistent with the informed consent of the research participants. Operationally, a documentation system has been developed in the form of a data use limitation statement or DUL. DULs are designed to document any uses of genomic data that are not authorized by the informed consent (National Institutes of Health, 2015). DULs are typically required for the submission to genomic databases. Investigators are required to provide DULs as part of the submission process, and a responsible Institutional Signing Official, typically an IRB administrator, must certify the form (National Institutes of Health, 2014). This certification step is logical given that the IRB is required to approve the consent form associated with the research protocol.

To facilitate the efficient and expeditious submission of genomic data to a sharing platform, investigators should obtain DULs from all databases they intend to deposit to. Prospective evaluation of data sharing considerations can inform the informed consent process and allow IRBs and ethics boards to ensure the approved protocol aligns with intended uses of data. Addressing genomic data use prospectively can also prevent delays that can result from retrospective analysis of research protocols. For example, an Institutional Signing Official who was not involved with approval of the original protocol may require additional time and information to certify a DUL.

Organizational excellence

This chapter has focused largely on steps to be taken in the context of materials acquisition, iPSC derivation, and product and data stewardship in iPSC derivation. These steps may be conceptualized as procedural actions necessary for policy compliance. However, thinking solely in terms of regulatory compliance misses the broader intent of policies intended to ensure donor autonomy, robust science, and responsible stewardship. Systems of informed consent, data protection, and information sharing/publication are processes that are subject to continuous quality improvement. They are also systems that are subject to failure (e.g., inappropriate subject identification, data breaches, etc.) if sustained efforts are not made to ensure process integrity.

With the benefit of administering hundreds of research awards over 15 years, I would suggest there are organizational features that enhance quality and guard against system failure. These organizational features include systematic procedures for developing research protocols where individuals with regulatory policy expertise are engaged at the earliest stages. In other words, scientists develop their programs alongside regulatory policy experts with a continuous working relationship. This team approach allows for early identification and mitigation of issues and builds a culture of team thinking where regulatory policy innovation occurs alongside scientific discovery and organizational excellence.

In contrast, in instances where there have been system failures, regulatory policy experts tend to be distal to the research team. This lack of integration tends to reinforce a compliance mentality where procedural actions are viewed as administrative hurdles rather than essential elements of the research protocol that are subject to innovation and continuous quality improvement.

Conclusion

iPSCs are powerful tools for advancing health research and therapy development. To optimize the potential of these tools, the research community should strive to ensure derived lines conform to national and international legal and ethical standards. This chapter provides a framework for navigating the regulatory and policy landscape to ensure that cell lines selection or iPSC derivation protocols are fit-for-purpose. Common considerations along the continuum of specimen acquisition, line derivation, and product management are identified, and recommendations provided to ensure research programs are on a robust regulatory footing. Science policy continues to evolve, often in response to societal concerns over the application of technologies that are increasingly transformative in their capacities to influence our understanding and response to health and disease. Given this evolving landscape, scientific organizations should strive for operational excellence where research protocols are developed in teams that include expertise in ethics and policy. Such organizations will serve to simultaneously advance biomedical research and build public trust.

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