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Jianyi Zhang Vahid Serpooshan Editors Advanced Technologies in Cardiovascular Bioengineering Advanced Technologies in Cardiovascular Bioengineering Jianyi Zhang • Vahid Serpooshan Editors Advanced Technologies in Cardiovascular Bioengineering Editors Jianyi Zhang Vahid Serpooshan Biomedical Engineering Biomedical Engineering University of Alabama at Birmingham Georgia Institute of Technology Birmingham, AL, USA Atlanta, GA, USA ISBN 978-3-030-86139-1 ISBN 978-3-030-86140-7 (eBook) https://doi.org/10.1007/978-3-030-86140-7 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Preface In recent decades, the convergence of discoveries in biological sciences and engineering have resulted in the development of new industries that offer the promise of revolutionary changes in society, as part of the Convergence Revolution (the Fourth Industrial Revolution). These advancements have offered the potential new management options for some of humanity’s most intractable and deadly diseases. Within the cardiovascular sciences, many of the most provocative discoveries have emerged from studies of pluripotent stem cells, whose roles in the medical sciences and physiological and injury response are becoming increasingly acknowledged. In 2016, the National Institutes of Health (NIH) established the Progenitor Cell Translational Consortium (PCTC) to support research into the use of stem and progenitor cells for both biology and therapeutic applications. This book was inspired by the thought-provoking ideas and observations presented at the 2019 PCTC Cardiovascular Bioengineering (CVBE) Symposium and was written by leading scientists and physicians whose work in the CVBE field spans decades and was conducted on four different continents. Cardiomyocytes in the hearts of humans and other mammals are largely incapa- ble of self-replicating; thus, although advancements in the clinical management of cardiovascular conditions have led to substantial improvements in patient longevity and quality of life, the scarring caused by cardiac disease or injury is essentially permanent. Myocardial integrity can be fully restored via whole-heart transplantation surgery, but the supply of donated hearts is far smaller than the number of patients who require treatment, so alternative strategies for replacing the myocardial scar with functional contractile tissue are urgently needed. The lack of cell-cycle activity in adult mammalian cardiomyocytes also severely restricts their availability for investigational work, so early studies of myocardial cell therapy were frequently conducted with stem cells which, though obtained from a variety of sources (e.g., the bone marrow, adipose tissue), were expected to differentiate into cardiomyocytes after transplantation. However, the benefits observed in subsequent clinical trials were only marginal and likely evolved from the cells’ paracrine activity, rather than through the production of new cardiomyocytes. v vi Preface The scarcity of cardiomyocytes for therapeutic investigations was alleviated by the isolation of human embryonic stem cells (ESCs) and, especially, by the development of techniques for reprogramming somatic cells into induced-pluripotent stem cells (iPSCs). Both cell types can proliferate indefinitely and are capable of differ- entiating into diverse cellular lineage; however, direct stem cell transplantation can lead to tumor formation; so, ESCs and iPSCs must be differentiated into more spe- cialized cell types before administration to patients, and only in recent years the differentiation protocols achieved the adequate efficiency to meet such demands. In general, the most effective protocols are modeled after the mechanisms that regulate cell specification during embryogenesis, when the four major lineages of cardiac cells evolve from progenitor cells of the first and second heart fields, the proepicar- dial organ, and the cardiac neural crest. These protocols may become even more efficient as researchers continue to refine and develop novel methods for determin- ing the identity, ancestry, and progeny of progenitor cells during development and as the heart recovers from injury. Only a small fraction of transplanted cells are engrafted within the native tissue and survives for more than a few days after administration, which is perhaps not surprising, since the cytotoxic conditions responsible for the loss of endogenous cells are likely to endure longer than the initial injury. One of the chief requirements of a more salubrious environment for transplanted cells is adequate perfusion. Both the size and thickness of engineered tissues are typically limited by the access of nutrients and signaling molecules to the cells within the tissue. Thus, the success of cell-based regenerative therapies for treatment of cardiac disease, as well as periph- eral artery disease, critical limb ischemia, and other predominantly vascular conditions, will depend on understanding the mechanisms by which the vascular cell differentiation and proliferation can be manipulated to promote vessel growth. Tissues constructed from human ESC- or iPSC-derived cells can also provide researchers with an entirely human-specific platform for studying the pathogenesis of disease and for testing new pharmaceutical products. Notably, iPSC-derived cell and tissue models are powerful tools for personalized therapies, because the iPSCs can be reprogrammed from the patient’s own somatic cells and, consequently, reca- pitulate all of the genetic factors that regulate disease pathology and progression, as well as the patient’s response to treatment. Autologous iPSC-derived cells are also expected to be minimally immunogenic when re-administered to the same patient for treatment of chronic conditions such as heart failure; however, the reprogramming and differentiation procedures take several weeks, so cell-based treatments for emergency situations, such as acute myocardial infarction, will require the use of allogeneic cells, which have rarely been studied. Furthermore, one of the primary concerns associated with cardiac cell therapy is the potential for arrhythmogenic complications caused by inadequate electromechanical coupling between the endogenous and transplanted cells. Thus, researchers continue to develop increasingly sophisticated tools for assessing the integration and electrophysiological function of engrafted cells and tissues, such as epicardial electrode arrays, genetically encoded fluorescent reporters, and catheter-based electroanatomic mapping. Preface vii Although the regenerative capacity of adult mammalian hearts is extremely limited, the hearts of at least some neonatal mammals (e.g., mice and pigs) can fully repair the damage caused by myocardial injury, provided that the injury occurs within the first few days after birth. Existing evidence suggests that this recovery is driven primarily by the proliferation of pre-existing cardiomyocytes, rather than the activity of stem or progenitor cells, which suggests that the cardiomyocytes of adult hearts may retain some latent proliferative capacity that could be therapeutically re-activated to improve cardiac performance in patients with heart disease. The mechanisms responsible for inducing proliferation in cardiomyocytes are just beginning to be explored. These works will be facilitated by advancements in single-c ell genomics, which can characterize the gene expression profiles of thou- sands of individual cells; however, the resulting datasets are typically so enormous that they require the use of modern data science techniques, such as dimensionality reduction and clustering analysis, to identify the genes and pathways that are dif- ferentially activated in proliferating and non-proliferating cardiomyocytes. Machine-learning algorithms can even be applied to the text mined from the Medline database and other unstructured sources to identify relationships among specific genes, diseases, and disease symptoms, including those that may explain why out- comes of COVID-19 treatment are worse for patients with cardiovascular comorbidities. In summary, many of the greatest advancements in science, and in civilization as a whole, have occurred when previously disparate lines of inquiry come together in unanticipated ways. The fields of personal and public health will soon reap the benefits of the unprecedented degree of synergy that has recently developed among the life and physical sciences, computing, and engineering. The authors of this book hope to foster these advancements by sharing their knowledge and expertise with the broader community of scientists, engineers, and clinicians. Birmingham, AL, USA Jianyi Zhang Atlanta, GA, USA Vahid Serpooshan Contents Part I Cardiac Development and Morphogenesis From Simple Cylinder to Four-Chambered Organ: A Brief Overview of Cardiac Morphogenesis . . . . . . . . . . . . . . . . . . . . . . . . 3 Carissa Lee, Sharon L. Paige, Francisco X. Galdos, Nicholas Wei, and Sean M. Wu Lineage Tracing Models to Study Cardiomyocyte Generation During Cardiac Development and Injury . . . . . . . . . . . . . . . . 15 Kamal Kolluri, Bin Zhou, and Reza Ardehali Mechanisms that Govern Endothelial Lineage Development and Vasculogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Daniel J. Garry and Javier E. Sierra-Pagan Part II C ellular Approaches to Cardiac Repair and Regeneration Remuscularization of Ventricular Infarcts Using the Existing Cardiac Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Yang Zhou and Jianyi Zhang Allogeneic Immunity Following Transplantation of Pluripotent Stem Cell-D erived Cardiomyocytes . . . . . . . . . . . . . . . . . . . 79 Yuji Shiba Vascular Regeneration with Induced Pluripotent Stem Cell-Derived Endothelial Cells and Reprogrammed Endothelial Cells . . . . . . . . . . . . . . 87 Sangho Lee and Young-sup Yoon The Guinea Pig Model in Cardiac Regeneration Research; Current Tissue Engineering Approaches and Future Directions . . . . . . . . 103 Tim Stüdemann and Florian Weinberger ix x Contents Part III Genetic Approaches to Study Cardiac Differentiation and Repair Analysing Genetic Programs of Cell Differentiation to Study Cardiac Cell Diversification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Zhixuan Wu, Sophie Shen, Yuliangzi Sun, Tessa Werner, Stephen T. Bradford, and Nathan J. Palpant Recombinant Adeno-Associated Virus for Cardiac Gene Therapy . . . . . . 169 Cindy Kok, Dhanya Ranvindran, and Eddy Kizana Part IV B ioengineering Approaches to Cardiovascular Tissue Modeling and Repair Microfabricated Systems for Cardiovascular Tissue Modeling . . . . . . . . . 193 Ericka Jayne Knee-Walden, Karl Wagner, Qinghua Wu, Naimeh Rafatian, and Milica Radisic Bioengineering of Pediatric Cardiovascular Constructs: In Vitro Modeling of Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . 233 Holly Bauser-Heaton, Carmen J. Gil, and Vahid Serpooshan Biomaterial Interface in Cardiac Cell and Tissue Engineering . . . . . . . . . 249 Chenyan Wang and Zhen Ma Stem Cell-Based 3D Bioprinting for Cardiovascular Tissue Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Clara Liu Chung Ming, Eitan Ben-Sefer, and Carmine Gentile Creating and Validating New Tools to Evaluate the Electrical Integration and Function of hPSC-Derived Cardiac Grafts In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 Wahiba Dhahri, Fanny Wulkan, and Michael A. Laflamme Part V C linical Perspectives Understanding the Molecular Interface of Cardiovascular Diseases and COVID- 19: A Data Science Approach . . . . . . . . . . . . . . . . . . 335 Dibakar Sigdel, Dylan Steinecke, Ding Wang, David Liem, Maya Gupta, Alex Zhang, Wei Wang, and Peipei Ping Clinical Application of iPSC-Derived Cardiomyocytes in Patients with Advanced Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 Jun Fujita, Shugo Tohyama, Hideaki Kanazawa, Yoshikazu Kishino, Marina Okada, Sho Tanosaki, Shota Someya, and Keiichi Fukuda Cell Therapy with Human ESC-Derived Cardiac Cells: Clinical Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375 Philippe Menasché Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 Part I Cardiac Development and Morphogenesis