Table Of ContentJianyi 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
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Preface
In recent decades, the convergence of discoveries in biological sciences and engi-
neering 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 man-
agement 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 pro-
genitor 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 transplanta-
tion 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 cardiomyo-
cytes 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 develop-
ment 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 condi-
tions, 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 reprogram-
ming 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 increas-
ingly sophisticated tools for assessing the integration and electrophysiological func-
tion 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 lim-
ited, 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 ben-
efits 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
