Recent Advances in iPSC Technology

The series Advances in Stem Cell Biology is a timely and expansive collection of comprehensive information and new discoveries in the field of stem cell biology.Recent Advances in iPSC Technology, Volume 5 addresses the progress in induced pluripotent stem cells (iPSCs) technologies.Somatic cells can be reprogrammed into iPSCs by the expression of specific transcription factors. These cells are transforming biomedical research in the last 15 years. The volume teaches readers about current advances in the field. This book describes different technologies and strategies to use iPSCs for biological and clinical benefit. 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. This volume will cover hot topics in the iPSC field, such as iPSCs for modeling the cardiovascular toxicities of anticancer therapies, iPSC differentiation through the lens of the noncoding genome, modeling of blood–brain barrier with iPSCs, mathematical modeling of iPSCs, iPSCs to study human brain evolution, selfrenewal in iPSCs, differences and similarities between iPSCs and embryonic stem cells, and more.The volume is written for researchers and scientists interested in stem cell therapy, cell biology, regenerative medicine, and organ transplantation and is contributed by world-renowned authors in the field.

• Provides overview of the fast-moving field of induced pluripotent stem cell technology, regenerative medicine, and therapeutics
• Covers the following topics: iPSCs for modeling the cardiovascular toxicities of anticancer therapies, iPSC differentiation through the lens of the non-coding genome, modeling of blood-brain barrier with iPSCs, mathematical modelling of iPSCs, iPSCs to study human brain evolution, self-renewal in iPSCs, differences and similarities between iPSCs and embryonic stem cells, and more
• Contributed by world-renown experts in the field

• Language: English
• Publisher: Academic Press
• Release date: Mar 31, 2021
• ISBN: 9780128223260

Book preview

Recent Advances in iPSC Technology, Volume 5

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

Chapter 1. Modeling the cardiovascular toxicities of anticancer therapies in the era of precision medicine

Introduction

Chemotherapy-associated cardiotoxicity

Modeling cardiotoxicity using iPSCs

Tissue engineering approaches with iPSCs

Moving forward: iPSC-based models for precision medicine

Conclusion

Chapter 2. Looking at induced pluripotent stem cell (iPSC) differentiation through the lens of the noncoding genome

Introduction

iPSC reprogramming from somatic cells

Differentiation of iPSC into somatic cells and validation of cell types differentiated from iPSC

lncRNAs as regulators of gene expression

Epigenetics

Epigenetic memory of iPSC

lncRNAs in iPSC differentiation

Epitranscriptomics

Commentary on future trends and directions

Chapter 3. In vitro blood–brain barrier model derived from human iPS cells and its applications

Introduction

General explanation about BBB

How to construct in vitro BBB model from iPSCs

Application of BBB model

A commentary on likely future directions

Chapter 4. The progress in the study of reprogramming to acquire the features of stem cells in iPSCs and cancers

Introduction

Similarity between tumorigenesis and the reprogramming process

Tumor suppression genes, oncogenes, and pluripotency-inducing factors in cancers and iPSCs

Regulation of cancer progression by hypoxia-inducing (transcription) factors (HIFs)

Features of CSCs

Epigenetic modification of the plasticity of CSCs

Strategies for avoiding tumorigenesis in PSCs and cancers

Enigmatic functions of JDP2 in tumor proliferation

Can we generate safe stem cells that do not possess a risk of tumorigenesis?

Conclusions and perspectives

Chapter 5. An introduction to the mathematical modeling of iPSCs

Introduction

Cell migration as a random walk

Differential equations

Agent-based modeling of colonies

iPSC-specific models

Discussion and prospects

Chapter 6. Use of iPSC-derived brain organoids to study human brain evolution

Introduction

A short historical background on human brain evolution studies

Evolution of the central nervous system and neurons

Genomic comparisons and what can be gained from them

The use of model organisms in relation to gene expression and cell biology

An introduction to iPSC-derived brain organoids

Studies using iPSC-derived brain organoids for human brain evolution

Future perspectives

Chapter 7. Self-renewal in induced pluripotent stem cells

Introduction to induced pluripotent stem cells

Cell cycle control in pluripotent stem cells

Cyclin-dependent kinases and cyclins

Cell cycle regulation in pluripotent stem cells

Links between pluripotency and cell cycle machinery

Cell cycle changes during reprogramming to pluripotency

The onset of differentiation is linked to the cell cycle

Growth factors implicated in self-renewal

Fibroblast growth factor

Transforming growth factor-β

Wnt/β-catenin signaling

Other mechanisms involved in the self-renewal of hiPSCs

Noncoding RNAs

MicroRNAs

miRNAs regulate self-renewal via the cell cycle

miRNAs as suppressors of pluripotency and self-renewal

lncRNAs

Telomere maintenance

Conclusions and outlook

Chapter 8. Strategies for iPSC expansion: from feeder cells to laminin

Introduction

PSC culture systems based on feeder cells

Matrigel, the first feeder-free system for maintaining pluripotency

Laminin, a xeno- and feeder-free system for cell expansion

Scaling-up human PSC expansion

Conclusion

Chapter 9. An overview of reprogramming approaches to derive integration-free induced pluripotent stem cells for prospective biomedical applications

Introduction

Nonintegrating approaches

Conclusion

Chapter 10. Induced pluripotent stem cells versus embryonic stem cells: a comprehensive overview of differences and similarities

Introduction

Transcriptional comparison

Epigenetic comparison

Proteomic comparison

Metabolomic comparison

Conclusion and future trends

Index

Advances in Stem Cell Biology

Series Editor

Alexander Birbrair

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1650, San Diego, CA 92101, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2021 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

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.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress

British Library Cataloguing-in-Publication Data

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

ISBN: 978-0-12-822231-7

For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci

Acquisitions Editor: Elizabeth Brown

Editorial Project Manager: Billie Jean Fernande

Production Project Manager: Omer Mukthar

Cover Designer: Mark Rogers

Typeset by TNQ Technologies

Dedication

This book is dedicated to my mother, Marina Sobolevsky, of blessed memory, who passed away during the creation of this volume. As 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 wife, Veranika, me, my daughter Tamar Ahava, and my beloved mom Marina Sobolevsky of blessed memory (July 28, 1959–June 3, 2020)

Contributors

Poulomi Adhikari

Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan

Dáša Bohačiaková,     Department of Histology and Embryology, Masaryk University, Faculty of Medicine, Brno, Czech Republic

Tomáš Bárta,     Department of Histology and Embryology, Masaryk University, Faculty of Medicine, Brno, Czech Republic

Giovanni Cuda

Research Center for Advanced Biochemistry and Molecular Biology, University of Catanzaro, Catanzaro, Italy

Department of Experimental and Clinical Medicine, University of Catanzaro, Catanzaro, Italy

Chandrima Dey,     Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

Logan Dunkenberger

Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, United States

Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

Michael H. Farkas

Department of Ophthalmology, State University of New York at Buffalo, Buffalo, NY, United States

Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, United States

VA Research Service, Veterans Affairs Western New York Healthcare System, Buffalo, NY, United States

Ranadeep Gogoi,     Department of Biotechnology, National Institute of Pharmaceutical Education and Research Guwahati, Mirza, Guwahati, Assam, India

Krishna Kumar Haridhasapavalan,     Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

Camila Hochman-Mendez,     Regenerative Medicine Research, Texas Heart Institute, Houston, TX, United States

Nadine J. Husami

Department of Ophthalmology, State University of New York at Buffalo, Buffalo, NY, United States

Department of Biochemistry, State University of New York at Buffalo, Buffalo, NY, United States

VA Research Service, Veterans Affairs Western New York Healthcare System, Buffalo, NY, United States

Ioannis Karakikes

Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, United States

Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

Kohsuke Kato,     Department of Infection Biology, Graduate School of Comprehensive Human Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan

Kenji Kawabata

Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Osaka, Japan

Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Osaka, Japan

M. Lako,     Bioscience Institute, Newcastle University, Newcastle upon Tyne, United Kingdom

Valeria Lucchino

Research Center for Advanced Biochemistry and Molecular Biology, University of Catanzaro, Catanzaro, Italy

Department of Experimental and Clinical Medicine, University of Catanzaro, Catanzaro, Italy

Fernanda C.P. Mesquita,     Regenerative Medicine Research, Texas Heart Institute, Houston, TX, United States

I. Neganova,     Institute of Cytology, RAS St. Petersburg, Russia

S. Orozco-Fuentes,     School of Mathematics, Statistics and Physics, Newcastle University, Newcastle upon Tyne, United Kingdom

Arpan Parichha,     Tata Institute of Fundamental Research, Mumbai, Maharashtra, India

N.G. Parker,     School of Mathematics, Statistics and Physics, Newcastle University, Newcastle upon Tyne, United Kingdom

Elvira Immacolata Parrotta

Research Center for Advanced Biochemistry and Molecular Biology, University of Catanzaro, Catanzaro, Italy

Department of Medical and Surgical Sciences, University of Catanzaro, Catanzaro, Italy

Khyati Raina,     Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

Orly Reiner,     Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

Shigeo Saito

Saito Laboratory of Cell Technology, Yaita, Tochigi, Japan

Waseda University Research Institute for Science and Engineering, Shinjuku, Tokyo, Japan

Tamar Sapir,     Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

Stefania Scalise

Research Center for Advanced Biochemistry and Molecular Biology, University of Catanzaro, Catanzaro, Italy

Department of Experimental and Clinical Medicine, University of Catanzaro, Catanzaro, Italy

Luana Scaramuzzino

Research Center for Advanced Biochemistry and Molecular Biology, University of Catanzaro, Catanzaro, Italy

Department of Experimental and Clinical Medicine, University of Catanzaro, Catanzaro, Italy

A. Shukurov,     School of Mathematics, Statistics and Physics, Newcastle University, Newcastle upon Tyne, United Kingdom

Pradeep Kumar Sundaravadivelu,     Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

Lukáš Čajánek,     Department of Histology and Embryology, Masaryk University, Faculty of Medicine, Brno, Czech Republic

Doris A. Taylor

Regenerative Medicine Research, Texas Heart Institute, Houston, TX, United States

RegenMedix Consulting, LLC, Houston, TX, United States

Madhuri Thool

Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

Department of Biotechnology, National Institute of Pharmaceutical Education and Research Guwahati, Mirza, Guwahati, Assam, India

Rajkumar P. Thummer,     Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India

L.E. Wadkin,     School of Mathematics, Statistics and Physics, Newcastle University, Newcastle upon Tyne, United Kingdom

Kenly Wuputra

Graduate Institute of Medicine, Kaohsiung Medical University, San-Ming District, Kaohsiung, Taiwan

Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, San-Ming District, Kaohsiung, Taiwan

Tomoko Yamaguchi,     Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Osaka, Japan

Kazunari K. Yokoyama

Graduate Institute of Medicine, Kaohsiung Medical University, San-Ming District, Kaohsiung, Taiwan

Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University Hospital, San-Ming District, Kaohsiung, Taiwan

Faculty of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo, Tokyo, Japan

Hongyan Zhang

Laboratory of Stem Cell Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Osaka, Japan

Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Osaka, Japan

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 (ABC), and in 2019, he was elected member of the Global Young Academy (GYA). He is the Founding Editor and Editor-in-Chief of Current Tissue Microenvironment Reports and Associate Editor of Molecular Biotechnology. Alexander also serves on 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 capable 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 Recent Advances 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-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-art techniques. These advantages facilitated identification of key targets and definition of the molecular basis of several disorders. Thus, the present 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. Ten chapters written by experts in the field summarize the present knowledge about iPSC technology.

Logan Dunkenberger and Ioannis Karakikes from Stanford University School of Medicine discuss iPSCs for modeling the cardiovascular toxicities of anticancer therapies. Nadine J. Husami and Michael H. Farkas from State University of New York at Buffalo look at iPSC differentiation through the lens of the noncoding genome. Kenji Kawabata and colleagues from Osaka University describe modeling of the blood–brain barrier with iPSCs. Shigeo Saito and colleagues from the University of Tokyo compile our understanding of the progress in the study of reprogramming to acquire the features of stem cells in iPSCs and cancers. Laura E. Wadkin and colleagues from Newcastle University update us with what we know about mathematical modeling of iPSCs. Orly Reiner and colleagues from Weizmann Institute of Science summarize current knowledge on the use of iPSC-derived brain organoids to study human brain evolution. Lukáš Čajánek and colleagues from Masaryk University talk about self-renewal in iPSCs. Doris A. Taylor and colleagues from Texas Heart Institute address the importance of strategies for iPSC expansion. Rajkumar P. Thummer and colleagues from Indian Institute of Technology Guwahati focus on approaches to derive integration-free iPSCs. Finally, Giovanni Cuda and colleagues from University of Catanzaro update us with the differences and similarities between iPSCs and embryonic stem cells.

It is hoped that the articles 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

Chapter 1: Modeling the cardiovascular toxicities of anticancer therapies in the era of precision medicine

Logan Dunkenberger ¹ , ² , and Ioannis Karakikes ¹ , ²       ¹ Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, United States      ² Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States

Abstract

Recent advances in cancer diagnosis and treatment have conferred drastic improvements in patient outcomes. With improved survivorship, cardiovascular diseases have emerged as a significant adverse effect of cancer treatment, increasing the demand for cardiooncology services. A broad range of chemotherapeutic agents have now been associated with adverse cardiovascular events and are likely to have significant effects on patient outcomes. It is, therefore, of intense and pressing interest to develop tractable preclinical models capable of elucidating the precise mechanisms of drug-induced cardiotoxicity. The emergence of new technologies, including human induced pluripotent stem cells (iPSCs), genome editing, and tissue engineering, offers a precision medicine-based strategy for the preclinical prediction of chemotherapy-associated cardiotoxicity. This chapter discusses recent advances in cardiotoxicity testing for anticancer therapies with an emphasis on iPSC-derived cardiovascular in vitro models.

Keywords

Anticancer; Cancer; Cardiomyocyte; Cardiooncology; Cardiotoxicity; Cardiovascular; Chemotherapy; Engineering; Genome editing; Induced pluripotent stem cells; Organoids; Organs-on-a-chip; Precision medicine; Preclinical models; Stem cells

Introduction

Chemotherapy-associated cardiotoxicity

Traditional chemotherapeutic agents

Targeted therapies

Modeling cardiotoxicity using iPSCs

Anthracyclines

Trastuzumab

Tyrosine kinase inhibitors

Tissue engineering approaches with iPSCs

Engineered heart tissues

Organ-on-a-chip

Moving forward: iPSC-based models for precision medicine

Conclusion

References

Introduction

Cancer is a leading cause of morbidity and mortality worldwide, second only to cardiovascular disease (Global Burden of Disease Collaborators, 2018). Novel diagnostic and therapeutic approaches have greatly improved cancer survivorship. However, the cardiotoxic effects of targeted cancer therapies have emphasized the importance of monitoring the cardiovascular health of cancer patients (Siegel et al., 2019; Daher et al., 2012). Chemotherapy-associated cardiovascular toxicity represents a heterogeneous group of clinical manifestations, leading to significant variation in its reported incidence. The most commonly used definition of cardiotoxicity described by the Cardiac Review and Evaluation Committee includes the following criteria: (i) a decline in left ventricular ejection fraction (LVEF) of 5% to <55% or 10% to <55% with or without symptoms of congestive heart failure, respectively; (ii) signs or symptoms of congestive heart failure; or (iii) cardiomyopathy characterized by LVEF decline (Seidman et al., 2002).

Impaired cardiovascular function secondary to chemotherapy has been observed in response to a wide array of nonselective cytotoxic and targeted molecular therapies. Traditional chemotherapies remain a staple of oncology practice, although their nonspecific cytotoxic activity leaves a significant potential for off-target effects. Interestingly, the incidence and severity of traditional chemotherapy-induced cardiovascular complications vary widely among patients, highlighting a possible genetic component of cardiotoxicity (Chang and Wang, 2018). Recently, cancer care has shifted from traditional chemotherapeutics to agents targeting specific molecular pathways crucial for cancer cell survival and proliferation. Nonetheless, cardiovascular toxicity has emerged as a severe complication associated with the introduction of novel therapeutic approaches and interventional strategies (Moslehi, 2016), emphasizing the need for a better understanding of the mechanisms underlying chemotherapy-induced cardiovascular dysfunction.

The emergence of induced pluripotent stem cells (iPSCs) (Takahashi and Yamanaka, 2006; Yu et al., 2007) and our refined capability to differentiate toward cardiovascular lineages, including iPSC-derived cardiomyocytes (Lian et al., 2013), smooth muscle (Dash et al., 2015), and endothelial cells (Choi et al., 2009), provide a new platform for preclinical cardiotoxicity screening of oncological drugs. Human iPSCs offer distinct advantages for drug screening, such as the ability to screen an individual patient’s cell responses (Burridge et al., 2016; Kitani et al., 2019) and increased biological relevance compared to animal models. Moreover, iPSC-derived cardiovascular cells are invaluable in advancing biomarker discovery and elucidating the underlying mechanisms of cardiotoxicity. Advances in tissue engineering offer strategies for the generation of microphysiological in vitro models with improved functional and structural aspects (Vunjak Novakovic et al., 2014), further increasing their biological relevance for cardiotoxicity screening. With the continually growing repertoire of cancer therapies, iPSC-based heart models provide an important in vitro tool for advancing the clinical translation of cardiooncology research.

Chemotherapy-associated cardiotoxicity

Traditional and targeted chemotherapies induce cardiovascular toxicity through varied mechanisms. Anthracyclines (Buzdar et al., 1985; Ryberg et al., 1998), alkylating agents (Gottdiener et al., 1981), antimetabolites (Polk et al., 2013), and microtubule inhibitors (Arbuck et al., 1993) are standard classes of traditional chemotherapeutics that exert nonselective cytotoxic activity and manifest clinically significant cardiovascular complications. Selective chemotherapies such as monoclonal antibodies (Baselga, 2001), angiogenesis inhibitors (Totzeck et al., 2017), and multitarget tyrosine kinase inhibitors (Orphanos et al., 2009) act on various cancer-associated signaling pathways and are also associated with a broad range of cardiovascular complications. Frequent manifestations of both traditional and targeted chemotherapy-induced cardiotoxicity include heart failure, vascular abnormalities, myocardial ischemia, arrhythmias, and hypertension. Cardiotoxicity data for conventional chemotherapies summarized in Table 1.1.

Table 1.1

Traditional chemotherapeutic agents

Anthracyclines, a widely used class of chemotherapeutic agents, are efficacious in solid and hematologic malignancies. However, these agents are frequently associated with irreversible cardiomyocyte damage and the subsequent onset of heart failure. The mechanisms underlying anthracycline toxicity are complex. Proposed mechanisms include DNA and mitochondrial damage via the generation of reactive oxygen species (ROS) (Chen et al., 2007; Volkova and Russell, 2011) and cardiomyocyte apoptosis mediated by topoisomerase IIB (TOP2B) dysfunction (McGowan et al., 2017; Lyu et al., 2007). Notably, anthracyclines frequently induce cardiomyocyte damage during treatment and cardiac dysfunction over a period of months to years that lead to the onset of congestive heart failure (Volkova and Russell, 2011). Pediatric cancer survivors, whose treatment regimens frequently include anthracycline therapy, are at an increased risk of heart failure in adulthood (Lipshultz et al., 2008).

Cyclophosphamide is an alkylating agent associated with significant cardiotoxicity when given in high doses (Gottdiener et al., 1981; Goldberg et al., 1986). Unlike the chronic nature of anthracycline-induced cardiotoxicity, cyclophosphamide-treated patients develop acute cardiomyopathy and heart failure within 3   weeks of treatment (Lee et al., 1996; Morandi et al., 2005). Postmortem examination suggests that cyclophosphamide-induced toxicity results from multiple complications, including endothelial damage, interstitial hemorrhage and edema, and pericarditis (Lee et al., 1996; Appelbaum et al., 1976). Increased dosage confers the highest risk of developing cardiac toxicity; however, the threshold for determining increased risk varies significantly from 100 to 270   mg/kg (Dhesi et al., 2013). Finally, other alkylating agents, such as ifosfamide and cisplatin, are associated with congestive heart failure and arrhythmias, especially with prior anthracycline therapy (Quezado et al., 1993). Finally, cisplatin is implicated in the development of hypertension, myocardial ischemia, and congestive heart failure (Patanè, 2014).

An antimetabolite agent, 5-fluorouracil (5-FU), is commonly used for the treatment of solid cancers and the second leading cause of cardiac toxicity (Polk et al., 2013; Anand, 1994; Sara et al., 2018). 5-FU inhibits cardiac function through direct cardiomyocyte damage, thrombus formation, and alteration of vascular smooth muscle function (Sara et al., 2018; Layoun et al., 2016). The precise molecular mechanisms of 5-FU cardiotoxicity remain unknown; preclinical studies have suggested that the accumulation of toxic metabolites leads to direct endothelial damage and myocardial ischemia resulting from coronary vasospasm as possible mechanisms of cardiac toxicity (Focaccetti et al., 2015; Mosseri et al., 1993). Chest pain, arrhythmias, and myocardial ischemia are the primary clinical manifestations of 5-FU toxicity, with life-threatening cardiotoxicity developing in <1% of patients (Anand, 1994; Alter et al., 2006).

Antimicrotubule agents, including taxanes, are also associated with myocardial ischemia and rhythm and conduction disturbances (Schimmel et al., 2004). Although cardiotoxicity is rarely associated with microtubule inhibitors alone, these agents are most commonly used in multiagent treatment regimens. For example, docetaxel and paclitaxel, are taxanes that, when used to treat breast cancer in combination with anthracyclines, augment the risk of cardiotoxicity (Lenneman and Sawyer, 2016).

Targeted therapies

Monoclonal antibodies have revolutionized cancer care and are used for the treatment of hematologic and solid malignancies. Several monoclonal antibodies are associated with adverse cardiovascular events. First, trastuzumab treatment has drastically improved the outcomes of HER2-positive breast cancers by selectively inhibiting the human epidermal growth factor receptor 2 (HER2) (Boekhout et al., 2011). However, trastuzumab therapy significantly increases the incidence of adverse cardiovascular events when used alone or in combination with taxanes or doxorubicin (Keefe, 2002). Second, bevacizumab, an angiogenesis inhibitor, blocks vascular endothelial growth factor (VEGF) signaling that drives tumor growth and metastasis, increases the risk for venous thromboembolism, hypertension, and heart failure alone or when used concurrently with anthracyclines (Yeh and Bickford, 2009; Chen and Ai, 2016; Economopoulou et al., 2015; Nalluri et al., 2008). Finally, alemtuzumab and rituximab, and cetuximab, approved therapies for hematologic and metastatic colon cancers, respectively, are shown to cause cardiotoxicity (Guan et al., 2015; Yeh et al., 2004).

Over the past decade, the small-molecule tyrosine kinase inhibitors (TKIs) transformed the approach to the management of various cancers, representing therapeutic breakthroughs with tremendous efficacy. Imatinib was one of the first cancer therapies to show the potential for such targeted action in chronic myeloid leukemia by inhibiting the kinase activity of Bcr-Abl. Nevertheless, kinase selectivity is often challenging because of the overlapping kinase activities in cancerous cells and myocardium, conferring significant risk for cardiovascular toxicity. Kerkelä et al. (2006) reported 10 patients who developed congestive heart failure following imatinib treatment attributed to endoplasmic reticulum stress response and mitochondrial dysfunction resulting from the inhibition of Bcr-Abl kinase. Since then, cardiotoxic effects are reported for several other TKIs. Both ponatinib and nilotinib can cause vascular toxicity (Moslehi and Deininger, 2015), while crizotinib causes QTc prolongation (Sahu et al., 2013) and bradycardia (Ou et al., 2013). Sorafenib and Sunitinib that inhibit VEGF and platelet-derived growth factor (PDGF) signaling are effective treatments against renal cell carcinoma and (Chu et al., 2007; Escudier et al., 2007). However, sorafenib is implicated in the development of myocardial ischemia and hypertension (Daher and Yeh, 2008; Force et al., 2007), likely mediated through VEGF inhibition and vascular dysfunction (Force et al., 2007). Sunitinib-mediated inhibition of PDGF receptor-β (PDGFRB) also causes severe impairment of the coronary microvasculature integrity by disrupting the pericyte–endothelial–cardiomyocyte coupling (Armulik et al., 2005; Chintalgattu et al., 2013; Touyz and Herrmann, 2018). Many patients treated with sunitinib experience a significant reduction in cardiac ejection fraction, hypertension, and heart failure (Chu et al., 2007; Daher and Yeh, 2008).

Modeling cardiotoxicity using iPSCs

The advent of human iPSC technology coupled with efficient differentiation protocols to generate cardiac lineages offers an authentic human preclinical model for cardiotoxicity screening to predict the risk of cardiovascular complications of cancer therapeutics. Cardiomyocytes derived from human iPSCs (iPSC-CMs) recapitulate critical features of human cardiomyocyte physiology, albeit their fetal-like phenotype (Karakikes et al., 2015). They can be used to screen a patient’s response to various chemotherapy regimens, identify biomarkers for monitoring cardiac function (Holmgren et al., 2015; Chaudhari et al., 2016), and for safety profiling of novel preclinical drugs (Koci et al., 2017), cementing their importance for cardiooncology research. Herein, we summarize the recent advances in the field.

Anthracyclines

To date, several studies have examined the utility of iPSC-CMs to assess the cardiotoxicity risk of chemotherapy agents, including doxorubicin (DOX), daunorubicin, epirubicin, and mitoxantrone. Most studies to date have focused on DOX as a model for anthracycline-induced cardiotoxicity. To demonstrate the applicability of iPSC-CMs as a cardiotoxicity screening model, Burridge et al. (2016) derived iPSCs from patients receiving DOX for breast cancer. Cardiomyocytes from patients who experienced DOX-induced cardiotoxicity showed increased sensitivity to doxorubicin toxicity compared to iPSC-CMs derived from patients without an adverse cardiovascular response to DOX treatment. This predilection to cardiotoxicity suggests that the iPSC-CMs offer a preclinical platform for uncovering the genetic basis and molecular mechanisms of chemotherapy-induced cardiotoxicity. Since then, several studies have explored the molecular mechanisms contributing to anthracycline cardiotoxicity. Maillet et al. (2016) validated the dose-dependent effect of DOX therapy on the levels of ROS, mitochondrial dysfunction, calcium mishandling, and cell apoptosis in iPSC-CMs. Mechanistically, the authors showed that disruption of TOP2B activity reduces the sensitivity of iPSC-CMs to DOX-induced apoptosis. More recently, it was demonstrated that iPSC-CMs exposed to DOX exhibited disorganized sarcomeres and abnormal mitochondrial distribution associated with the downregulation of cardiac troponin T and cardiac troponin I (Adamcova et al., 2019). Similarly, Gupta et al. (2018) revealed a novel mechanism for DOX-induced cardiotoxicity involving the downregulation of the RNA binding protein quaking (QKI). Interestingly, overexpression of QKI offered protection from doxorubicin cardiotoxicity via the regulation of circRNAs, including TTN, FHOD3, and STRN3.

Several studies have demonstrated transcriptomic profiling of iPSC-CMs as a valuable approach to identify biomarkers for anthracycline-induced cardiovascular toxicity. First, gene expression analysis of arrhythmogenic iPSC-CMs exposed to DOX identified a panel of 84 differentially expressed genes associated with cardiac function, stress, and apoptosis (Chaudhari et al., 2016). Comparative analysis of daunorubicin and mitoxantrone-treated iPSC-CMs identified 35 common dysregulated genes as biomarkers of anthracycline cardiotoxicity. Second, investigation of DOX-induced transcriptomic changes in iPSC-CMs identified the tumor suppressor protein p53 and activation of death receptor signaling as critical regulators of DOX-induced cardiotoxicity (McSweeney et al., 2019). A separate study corroborated these findings, suggesting that the upregulation of death receptor is as an early biomarker of DOX-induced cardiotoxicity (Zhao and Zhang, 2017). Third, Holmgren et al. (2015) investigated iPSC-CM gene expression profiles after 48   h of DOX treatment and a 12-day recovery period to identify dysregulated gene signatures during and after treatment. While expression of cardiac troponin T was an accurate indicator of acute toxicity, genes that remain differentially expressed after DOX exposure, including a possible cardiotoxicity biomarker GDF15, offered improved accuracy for indicating late-onset cardiotoxicity. Finally, DOX toxicity-associated cardiac biomarkers, cardiac troponin I, and N-terminal probrain natriuretic peptide have been validated in iPSC-CMs (Kopljar et al., 2017). These studies suggest that iPSC-CMs could provide a valuable platform for the discovery of biomarkers associated with anthracycline-induced cardiotoxicity.

Trastuzumab

Preclinical predictors for targeted chemotherapy-induced cardiotoxicity remain ineffective. Patient-derived iPSC-CMs studies have demonstrated promise for the preclinical modeling of trastuzumab-associated cardiotoxicity. One recent study described the ability of iPSC-CMs to recapitulate patient responses to trastuzumab therapy (Kitani et al., 2019). iPSC-CMs derived from patients who experienced trastuzumab-associated cardiotoxicity exhibited impaired contraction and calcium handling following trastuzumab treatment. Disruption of mitochondrial and metabolic function, both hallmarks of trastuzumab-induced cardiovascular dysfunction, were evident in trastuzumab-treated cells; however, cardiomyocytes retained cell viability and typical sarcomere organization. Other studies have explored mechanisms of trastuzumab-induced cardiotoxicity using iPSC-CMs. Using a transcriptomics approach, Necela et al. (2017) found that trastuzumab-induced ErbB2 inhibition dysregulates genes associated with ischemic injury and metabolism. A separate study reported that inhibition of ErbB signaling by trastuzumab aggravated doxorubicin-induced damage in iPSC-CMs, while ErbB activation by neuregulin was protective (Eldridge et al., 2014). Finally, using a coculture model of iPSC-CMs and iPSC-derived endothelial cells (iPSC-ECs), Kurokawa et al. (2018) demonstrated that trastuzumab is blocking the cardioprotective effects of the ErbB2/4 pathway. Collectively, these results support the expanded use of human iPSC-based models to delineate the mechanisms of cardiotoxicity and support the value of using these models in early preclinical assessments of cardiotoxicity.

Tyrosine kinase inhibitors

As TKIs have become the staples of oncology clinical practice, cardiovascular toxicity has emerged as a severe consequence of their use. Despite its growing prevalence, little is known about the mechanisms of TKI cardiotoxicity. Recent studies have explored the utility of iPSC-CM models to gain a better understanding of the underlying mechanisms of TKI-induced cardiotoxicity. Cohen et al. (2011) investigated the mechanism of sunitinib cardiotoxicity. Unlike rodent models, which have suggested a causative role for AMPK and RSK, cardiotoxicity was not induced by selective RSK inhibition or alleviated by AMPK activation in iPSC-CMs. Still, sunitinib induced dose-dependent cardiotoxicity in iPSC-CMs, which was reflected in mitochondrial dysfunction and cardiomyocyte apoptosis, highlighting key differences in human and rodent models of drug toxicity. A separate study found that lapatinib, an EGFR inhibitor commonly used in trastuzumab-resistant patients, potentiated DOX toxicity in iPSC-CMs by increasing NO production (Hsu et al., 2018). Using a comprehensive in vitro screen, Talbert et al. (2015) found that ponatinib treatment significantly altered cardiomyocyte survival, mitochondrial function, and beating rate of iPSC-CMs. Mechanistically, the authors identified disruption of the actin cytoskeleton and inhibition of prosurvival pathways ABL, AKT, and ERK as possible mechanisms of ponatinib toxicity. The same group also evaluated the toxicity profiles of crizotinib, sunitinib, nilotinib, and erlotinib (Doherty et al., 2013). Their multiparameter approach accurately classified crizotinib, sunitinib, and nilotinib as cardiotoxic, while the relatively cardiac safe drug, erlotinib, did not significantly alter cardiomyocyte function. Each cardiotoxic drug exhibited a unique toxicity profile, including induction of apoptosis, altered beat-to-beat pattern, lipid accumulation, and increased ROS production, emphasizing the utility of iPSC-CM screening for preclinical drug development. Sharma et al. (2017) developed a cardiac safety index for 21 TKIs using a high-throughput functional