Heart disease is the leading cause of death worldwide, and each year over 1 million Americans suffer from a myocardial infarction, with many subsequently developing heart failure. Our labs have worked extensively to develop next-generation therapies for heart failure based upon remuscularizing the scar with stem cell-derived cardiomyocytes. While promising, these immature cells fail to recapitulate the adult cardiomyocyte phenotype and lack the ability to generate meaningful force, which may explain the relatively modest gains in cardiac function seen in most studies to date. Motivated by this challenge, I hypothesized that developing novel strategies to improve the contractile performance of human pluripotent stem cell-derived cardiomyocytes will improve the efficacy of cardiac cell therapy. My thesis work has focused on developing two independent strategies to improve the contractile capabilities of these cells. First, I developed a novel maturation process whereby immature cardiomyocytes begin to recapitulate key structural and functional characteristics of mature adult cardiomyocytes. These cells become larger and more directional, exhibit highly organized intracellular contractile machinery, and demonstrate improved contractility, Ca2+-handling, and action potential characteristics. I then worked to develop a second approach based on the small molecule dATP, which our lab has shown dramatically increases cardiac function by substituting for ATP as the energy substrate for cardiac myosin. Based upon preliminary studies, I hypothesized that like other small metabolites, dATP is capable of crossing gap junctions and diffusing between neighboring cells. Using several independent techniques, I confirmed this phenomenon and subsequently showed that transplanting stem cell-derived cardiomyocytes overexpressing ribonucleotide reductase, the enzyme that synthesizes dATP, dramatically improves global heart function via gap junction-mediated dATP transfer. Based upon these studies, our lab is currently testing both approaches in models of myocardial infarction, with hopes of one day translating these approaches to a future clinical therapy for heart failure.

This Volume of the series Cardiac and Vascular Biology offers a comprehensive and exciting, state-of-the-art work on the current options and potentials of cardiac regeneration and repair. Several techniques and approaches have been developed for heart failure repair: direct injection of cells, programming of scar tissue into functional myocardium, and tissue-engineered heart muscle support. The book introduces the rationale for these different approaches in cell-based heart regeneration and discusses the most important considerations for clinical translation. Expert authors discuss when, why, and how heart muscle can be salvaged. The book represents a valuable resource for stem cell researchers, cardiologists, bioengineers, and biomedical scientists studying cardiac function and regeneration.

There is great potential for human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) to serve as a test bed for developmental, pharmacological, and regenerative studies. These cells can serve as therapeutic agents, which can be implanted into damage heart tissue to supplant dead cells. They can be used to assess new pharmacological treatments for heart disease. Moreover, they can be used as model systems to study the progression of developmental and pathological states of the heart. However, upon differentiation into cardiomyocytes, these cells are distinctly immature i.e. their cell size, shape, cardiac-specific markers, ploidy, nucleation, calcium handling properties, action potentials, contractility, metabolism, etc. more closely mimic that of an embryonic-stage cardiomyocyte. Therefore, in order for these cells to serve as a valid replacement or model for more developed cardiomyocytes, their structural and functional maturation must be assessed and enhanced. One of the most important functional characteristics of a cardiomyocyte is its ability to produce contractile forces. Therefore, having the ability to quantify this contraction would provide a powerful assessment tool for hPSC-CMs. Arrays of micropost have previously been employed as a means to measure the isotonic contraction of cardiomyocytes. In this work, a new micropost technique was developed in order to allow for real-time measurements of hPSC-CM contractility, to enable contractile assessment under various different culture conditions. Previous studies with immature cardiomyocytes have shown that a number of different methods are able to enhance their contractile and structural maturation. Here, hPSC-CM maturation was achieved via: i) prolonged cell culture, ii) cell alignment, iii) controlling cell-cell contact between adjacent cells, iv) altering substrate stiffness, v) electrically-stimulating the cells, and vii) treating the cells with various different biochemical agents. Assessment of hPSC-CM structural maturation was achieved by immunofluorescent analysis, while high speed imaging of micropost deflections and fluorescent calcium transients was used to quantify functional maturation. Through these studies, I found that the micropost assay is capable of accessing the contractile state of immature human cardiomyocytes, which makes it a powerful tool for developmental studies, pharmacological screening, and disease modeling applications. Furthermore, the pro-maturation environment that I developed was able to elicit cardiomyocyte maturation in the absence of any biochemical cues. Ultimately, I believe that these novel culture and analysis techniques will provide future researchers with a means to culture large populations of rapidly matured stem cell-derived cardiomyocytes, in order to effectively perform developmental, pharmacological, and therapeutic studies in a more rapid and high-throughput manner.

Medical research made huge strides in treating heart disease in the 20th century, from drug-eluding stents to automatic internal defibrillators. Public awareness of the dangers of heart disease has never been more pervasive. Now, though, ten years into a new millennium, scientists are gearing up for the next great challenges in tackling this pervasive condition. Cell therapy is going to be a key weapon in the fight against heart disease. It has the potential to address many cardiovascular conditions. From heart failure to atrioventricular nodal dysfunction, the young but promising field of cell therapy is set to play a significant role in developing the cures that the upcoming decades of hard work will yield. Regenerating the Heart: Stem Cells and the Cardiovascular System organizes the field into a digestible body of knowledge. Its four sections cover mechanical regeneration, electrical regeneration, cardiac tissues and in vivo stem cell therapies. An array of talented researchers share the fruits of their labors, with chapters covering such crucial issues as the cardiogenic potential of varying stem cell types, the ways in which they might be used to tackle arrhythmias, their possible application to biological replacements for cardiac tissues such as valves, and the varying approaches used in the in vivo evaluation of stem cell therapies, including methods of delivering stem cells to the myocardium. This comprehensive survey of an area of research with such exciting potential is an invaluable resource both for veteran stem cell researchers who need to monitor fresh developments, and for newly minted investigators seeking inspirational examples.

This book is a comprehensive and up-to-date resource on the use of regenerative medicine for the treatment of cardiovascular disease. It provides a much-needed review of the rapid development and evolution of bio-fabrication techniques to engineer cardiovascular tissues as well as their use in clinical settings. The book incorporates recent advances in the biology, biomaterial design, and manufacturing of bioengineered cardiovascular tissue with their clinical applications to bridge the basic sciences to current and future cardiovascular treatment. The book begins with an examination of state-of-the-art cellular, biomaterial, and macromolecular technologies for the repair and regeneration of diseased heart tissue. It discusses advances in nanotechnology and bioengineering of cardiac microtissues using acoustic assembly. Subsequent chapters explore the clinical applications and translational potential of current technologies such as cardiac patch-based treatments, cell-based regenerative therapies, and injectable hydrogels. The book examines how these methodologies are used to treat a variety of cardiovascular diseases including myocardial infarction, congenital heart disease, and ischemic heart injuries. Finally, the volume concludes with a summary of the most prominent challenges and perspectives on the field of cardiovascular tissue engineering and clinical cardiovascular regenerative medicine. Cardiovascular Regenerative Medicine is an essential resource for physicians, residents, fellows, and medical students in cardiology and cardiovascular regeneration as well as clinical and basic researchers in bioengineering, nanomaterial and technology, and cardiovascular biology.

Myocardial tissue engineering (MTE), a concept that intends to prolong patients’ life after cardiac damage by supporting or restoring heart function, is continuously improving. Common MTE strategies include an engineered ‘vehicle’, which may be a porous scaffold or a dense substrate or patch, made of either natural or synthetic polymeric materials. The function of the substrate is to aid transportation of cells into the diseased region of the heart and support their integration. This book, which contains chapters written by leading experts in MTE, gives a complete analysis of the area and presents the latest advances in the field. The chapters cover all relevant aspects of MTE strategies, including cell sources, specific TE techniques and biomaterials used. Many different cell types have been suggested for cell therapy in the framework of MTE, including autologous bone marrow-derived or cardiac progenitors, as well as embryonic or induced pluripotent stem cells, each having their particular advantages and disadvantages. The book covers a complete range of biomaterials, examining different aspects of their application in MTE, such as biocompatibility with cardiac cells, mechanical capability and compatibility with the mechanical properties of the native myocardium as well as degradation behaviour in vivo and in vitro. Although a great deal of research is being carried out in the field, this book also addresses many questions that still remain unanswered and highlights those areas in which further research efforts are required. The book will also give an insight into clinical trials and possible novel cell sources for cell therapy in MTE.

This book is the definitive reference on two of the most exciting areas of cardiovascular research – myocardial regeneration and stem cell therapy – for the treatment of disease. Edited by pioneers in the area, with contributions from every major investigator worldwide, it covers: The biology of stem cells The actions of stem cells from the bone marrow, the heart, and embryos on the normal restorative and repair functions of the heart and blood vessels How stem cells could contribute to myocardial recovery in the face of injury and aging How adjuvant therapy with growth factors might enhance stem cell activity in regeneration and repair Clinical applications and clinical experiences This fully referenced publication presents the current state of knowledge in both basic science and clinical practice, and is an essential reference for scientists, students, and clinicians.