Cardiac regeneration strategies Tzahor, Eldad; Poss, Kenneth D.
Science (American Association for the Advancement of Science),
06/2017, Letnik:
356, Številka:
6342
Journal Article
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The human heart is continually operating as a muscular pump, contracting, on average, 80 times per minute to propel 8000 liters of blood through body tissues each day. Whereas damaged skeletal muscle ...has a profound capacity to regenerate, heart muscle, at least in mammals, has poor regenerative potential. This deficiency is attributable to the lack of resident cardiac stem cells, combined with roadblocks that limit adult cardiomyocytes from entering the cell cycle and completing division. Insights for regeneration have recently emerged from studies of animals with an elevated innate capacity for regeneration, the innovation of stem cell and reprogramming technologies, and a clearer understanding of the cardiomyocyte genetic program and key extrinsic signals. Methods to augment heart regeneration now have potential to counteract the high morbidity and mortality of cardiovascular disease.
Questions about how and why tissue regeneration occurs have captured the attention of countless biologists, biomedical engineers and clinicians. Regenerative capacity differs greatly across organs ...and organisms, and a range of model systems that use different regenerative strategies and that offer different technical advantages have been studied to understand regeneration. Making use of this range of systems and approaches, recent advances have allowed progress to be made in understanding several key issues that are common to natural regenerative events. These issues include: the determination of regenerative capacity; the importance of stem cells, dedifferentiation and transdifferentiation; how regenerative signals are initiated and targeted; and the mechanisms that control regenerative proliferation and patterning.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
After decades of directed research, no effective regenerative therapy is currently available to repair the injured human heart. The epicardium, a layer of mesothelial tissue that envelops the heart ...in all vertebrates, has emerged as a new player in cardiac repair and regeneration. The epicardium is essential for muscle regeneration in the zebrafish model of innate heart regeneration, and the epicardium also participates in fibrotic responses in mammalian hearts. This structure serves as a source of crucial cells, such as vascular smooth muscle cells, pericytes, and fibroblasts, during heart development and repair. The epicardium also secretes factors that are essential for proliferation and survival of cardiomyocytes. In this Review, we describe recent advances in our understanding of the biology of the epicardium and the effect of these findings on the candidacy of this structure as a therapeutic target for heart repair and regeneration.
The adult human heart does not regenerate significant amounts of lost tissue after injury. Rather than making new, functional muscle, human hearts are prone to scarring and hypertrophy, which can ...often lead to fatal arrhythmias and heart failure. The most-cited basis of this ineffective cardiac regeneration in mammals is the low proliferative capacity of adult cardiomyocytes. However, mammalian cardiomyocytes can avidly proliferate during fetal and neonatal development, and both adult zebrafish and neonatal mice can regenerate cardiac muscle after injury, suggesting that latent regenerative potential exists. Dissecting the cellular and molecular mechanisms that promote cardiomyocyte proliferation throughout life, deciphering why proliferative capacity normally dissipates in adult mammals, and deriving means to boost this capacity are primary goals in cardiovascular research. Here, we review our current understanding of how cardiomyocyte proliferation is regulated during heart development and regeneration.
The heart holds the monumental yet monotonous task of maintaining circulation. Although cardiac function is critical to other organs and to life itself, mammals are not equipped with significant ...natural capacity to replace heart muscle that has been lost by injury. This deficiency plays a role in leaving millions worldwide vulnerable to heart failure each year. By contrast, certain other vertebrate species such as zebrafish are strikingly good at heart regeneration. A cellular and molecular understanding of endogenous regenerative mechanisms and advances in methodology to transplant cells together project a future in which cardiac muscle regeneration can be therapeutically stimulated in injured human hearts. This review focuses on what has been discovered recently about cardiac regenerative capacity and how natural mechanisms of heart regeneration in model systems are stimulated and maintained.
Zebrafish heart regeneration occurs through the activation of cardiomyocyte proliferation in areas of trauma. Here, we show that within 3 hr of ventricular injury, the entire endocardium undergoes ...morphological changes and induces expression of the retinoic acid (RA)-synthesizing enzyme
raldh2. By one day posttrauma,
raldh2 expression becomes localized to endocardial cells at the injury site, an area that is supplemented with
raldh2-expressing epicardial cells as cardiogenesis begins. Induced transgenic inhibition of RA receptors or expression of an RA-degrading enzyme blocked regenerative cardiomyocyte proliferation. Injured hearts of the ancient fish
Polypterus senegalus also induced and maintained robust endocardial and epicardial
raldh2 expression coincident with cardiomyocyte proliferation, whereas poorly regenerative infarcted murine hearts did not. Our findings reveal that the endocardium is a dynamic, injury-responsive source of RA in zebrafish, and indicate key roles for endocardial and epicardial cells in targeting RA synthesis to damaged heart tissue and promoting cardiomyocyte proliferation.
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► Cardiac injury induces structural and molecular changes in zebrafish endocardium ► Endocardial and epicardial cells at the site of injury synthesize retinoic acid (RA) ► The extent of this injury response correlates with a species' regenerative capacity ► Regenerative cardiomyocyte proliferation in zebrafish requires retinoic acid signaling
Regeneration is the process by which organisms replace lost or damaged tissue, and regenerative capacity can vary greatly among species, tissues and life stages. Tissue regeneration shares certain ...hallmarks of embryonic development, in that lineage-specific factors can be repurposed upon injury to initiate morphogenesis; however, many differences exist between regeneration and embryogenesis. Recent studies of regenerating tissues in laboratory model organisms - such as acoel worms, frogs, fish and mice - have revealed that chromatin structure, dedicated enhancers and transcriptional networks are regulated in a context-specific manner to control key gene expression programmes. A deeper mechanistic understanding of the gene regulatory networks of regeneration pathways might ultimately enable their targeted reactivation as a means to treat human injuries and degenerative diseases. In this Review, we consider the regeneration of body parts across a range of tissues and species to explore common themes and potentially exploitable elements.
As vertebrate embryos develop to adulthood, their organs undergo marked changes in size and tissue architecture. The heart acquires muscle mass and matures structurally to fulfil increasing ...circulatory needs, a process that is incompletely understood. Here we used multicolour clonal analysis to define the contributions of individual cardiomyocytes as the zebrafish heart undergoes morphogenesis from a primitive embryonic structure into its complex adult form. We find that the single-cardiomyocyte-thick wall of the juvenile ventricle forms by lateral expansion of several dozen cardiomyocytes into muscle patches of variable sizes and shapes. As juvenile zebrafish mature into adults, this structure becomes fully enveloped by a new lineage of cortical muscle. Adult cortical muscle originates from a small number of cardiomyocytes--an average of approximately eight per animal--that display clonal dominance reminiscent of stem cell populations. Cortical cardiomyocytes initially emerge from internal myofibres that in rare events breach the juvenile ventricular wall, and then expand over the surface. Our results illuminate the dynamic proliferative behaviours that generate adult cardiac structure, revealing clonal dominance as a key mechanism that shapes a vertebrate organ.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights • The zebrafish is a key genetic model system for vertebrate regeneration research. • Toolsets continue to evolve for studies of zebrafish appendage, heart, and neural regeneration. • ...Regeneration concepts and mechanisms in zebrafish have implications for mammals.
Unlike adult mammals, adult zebrafish vigorously regenerate lost heart muscle in response to injury. The epicardium, a mesothelial cell layer enveloping the myocardium, is activated to proliferate ...after cardiac injury and can contribute vascular support cells or provide mitogens to regenerating muscle. Here, we applied proteomics to identify secreted proteins that are associated with heart regeneration. We found that Fibronectin, a main component of the extracellular matrix, is induced and deposited after cardiac damage. In situ hybridization and transgenic reporter analyses indicated that expression of two fibronectin paralogues, fn1 and fn1b, are induced by injury in epicardial cells, while the itgb3 receptor is induced in cardiomyocytes near the injury site. fn1, the more dynamic of these paralogs, is induced chamber-wide within one day of injury before localizing epicardial Fn1 synthesis to the injury site. fn1 loss-of-function mutations disrupted zebrafish heart regeneration, as did induced expression of a dominant-negative Fibronectin cassette, defects that were not attributable to direct inhibition of cardiomyocyte proliferation. These findings reveal a new role for the epicardium in establishing an extracellular environment that supports heart regeneration.
•The epicardium produces the ECM component Fibronectin in response to cardiac injury.•Dynamic Fibronectin induction starts organ-wide and then localizes to injury.•Fibronectin receptor integrin β3 is induced in cardiomyocytes near the injury site.•Loss-of-function approaches indicate Fibronectin is required for heart regeneration.•Fibronectin loss-of-function does not directly inhibit cardiomyocyte proliferation.
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