In vivo cardiac reprogramming contributes to zebrafish heart regeneration article pdf available in nature 4987455 june 20 with 315 reads how we measure reads. Chla researchers discover a mechanism of heart regeneration in zebrafish. Natural models of heart regeneration in lower vertebrates such as zebrafish are based on invasive surgeries causing mechanical injuries that are limited in size. The regenerative capacity of zebrafish reverses cardiac failure. Our data show that the migration of cms into the injury site is regulated independently of proliferation, and that coordination of both processes is essential for heart regeneration. The animation illustrates the steps in this regeneration process, highlighting the role of cell signaling proteins called fibroblast growth factors fgf. Here, we created a genetic cell ablation model in zebrafish that facilitates inducible destruction of a high percentage of cardiomyocytes. Cell migration during heart regeneration in zebrafish ncbi nih. Advances in understanding the mechanism of zebrafish heart regeneration. An important mechanistic feature of zebrafish heart regeneration was revealed by recent. The formation of skeletal muscle fibers during embryogenesis and adult injuryinduced muscle repair occurs through the fusion of myoblasts. Myocardial polyploidization creates a barrier to heart regeneration in. Pdf a chemical biology approach to myocardial regeneration.
The zebrafish heart regenerates after cryoinjuryinduced. Zebrafish heart regeneration as a model for cardiac tissue. Collectively, our study identifies h3k27me3mediated silencing of structural genes as requisite for zebrafish heart regeneration and suggests that repression of similar structural components in the border zone of an infarcted human heart might improve its regenerative capacity. Genetic ablation of regulatory tcells, which circulate and home to the injury site, impairs heart regeneration and other examples of tissue regeneration in zebrafish 27. Myomixer and myomaker, another musclespecific membrane protein, are sufficient to induce fusion of nonmuscle cells. Unlike humans, many lower vertebrates readily regenerate limbs, appendages and internal organs after injury. Neonatal mouse heart regeneration is similar to zebrafish heart regeneration, involving cardiomyocyte dedifferentiation and proliferation. While heart regeneration is generally very low in mammals, it can regenerate efficiently in certain amphibian and fish species 4,5. Individual channels were merged in imagej software schneider et al. Teleosts, as urodele amphibians, have the remarkable capacity to regenerate several organs and structures of their body after an injury.
Regeneration occurs through robust proliferation of cardiomyocytes localized at the leading epicardial edge of the new myocardium. Tbx5a lineage tracing shows cardiomyocyte plasticity. A metabolic switch from oxphos to glycolysis is essential. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. In contrast to humans and other mammals, zebrafish hearts regenerate after substantial injury or tissue damage. We recently discovered myomixer, a musclespecific micropeptide required for myoblast fusion in mice.
The most significant risk factors associated with the development of heart diseases include genetic and environmental factors such as hypertension, high blood cholesterol levels, diabetes, smoking, and obesity. Requirement of the fusogenic micropeptide myomixer for. However, a damaged zebrafish heart can recover most of its original shape, size, and function over time. A combination of forward genetic screens, large clutch size, and external development has made the zebrafish a popular model system for ontogenetic development.
Department of cell biology, duke university medical center, durham, nc 27710, united states available online 24 november 2006 abstract a scienti. Zebrafish, regeneration, scarring, heart failure, inflammation. Therefore, elucidating mechanisms of zebrafish heart regeneration. Zebrafish models of cardiovascular disease springerlink. The zebrafish is an established model organism to study heart regeneration, in which preexisting cardiomyocytes proliferate to replace the lost. Migration of cardiomyocytes is essential for heart.
There is a long history of research in amphibian heart regeneration 9. Cardiac injury in mammals and amphibians typically leads to scarring, with minimal regeneration of heart muscle. Zebrafish cardiomyocytes were assumed to be diploid based on their. Cardiovascular disease cvd is one of the leading causes of death worldwide. A chemical biology approach to myocardial regeneration. Zebrafish, which any of you who are fish fans here, keep. Primary contribution to zebrafish heart regeneration by. Mammals respond to a myocardial infarction by irreversible scar formation. Regeneration is a complex biological process by which animals restore the shape, structure and function of body parts lost to injury or experiment brockes and kumar, 2005. Pdf despite current treatment regimens, heart failure remains the leading.
Several nonmammalian vertebrates, including zebrafish, possess the. Recent work has shown that mg give rise to regenerated retinal neurons, but the role of resident microglia, and the innate immune system more generally, during retinal. By contrast, teleost fish and urodele amphibians are capable of heart regeneration after a partial amputation. Autophagic vesicle formation in the heart ventricle is increased during zebrafish cardiac regeneration. One of the most remarkable examples is heart regeneration ausoni and sartore, 2009.
Tbx5a lineage tracing shows cardiomyocyte plasticity during. Stem cell research heart regeneration and rejuvenation. Zebrafish heart regeneration developmental biology. This is a pdf file of an unedited manuscript that has been. In particular, hypoxia is associated with cardiac ischemia. Here, we demonstrate histologically that zebrafish fully regenerate hearts within 2 months of 20% ventricular resection. Complete tissue regeneration of multiple organs, including the heart, has been demonstrated in several vertebrate model systems such as the zebrafish.
The asterisk marks a large blood clot adjacent to the left ventricular chamber arrow at 1 and 2 dpr. Notch signalling is required for zebrafish cardiac regeneration. The capacity to regenerate damaged tissues, such as the heart, various enormously amongst species. Telomerase is essential for zebrafish heart regeneration. Cellspecific depletion of over 60% of the ventricular myocardium triggered signs of cardiac. In adult zebrafish and neonatal mice, heart regeneration occurs primarily through proliferation of preexisting cardiomyocytes 1, 2. Zebrafish has been used extensively to study heart regeneration, resulting in the identification of proliferating cardiomyocytes that drive this.
Regeneration of the central nervous systemprinciples from. Autophagy activation in zebrafish heart regeneration. Electron microscopy shows a high degree of tissue remodeling of. Zebrafish heart regeneration occurs by cardiomyocyte. Zebrafish heart regeneration process uab barcelona. During heart regeneration in zebrafish, lost ventricular tissues is rapidly replaced.
The regenerative capacity of the zebrafish heart is. An important difference is that injuryinduced cardiogenesis occurs throughout the injured, growing organ in mice, whereas in hearts of mature zebrafish this response is focused at the injury site. Regeneration of the central nervous systemprinciples from brain regeneration in adult zebrafish. Dual roles of hydrogen peroxide in promoting zebrafish. Its got a little heart with just two chambers, one atrium and one ventricle, and that pumps blood throughout the whole body, past the gills, which are the equivalent of a lung.
The study of zebrafish as a leading model organism for developmental biology is rapidly expanding. Hypoxia induces myocardial regeneration in zebrafish circulation. The exact source of these new cardiomyocytes is an unanswered question. The zebrafish is an established model organism to study heart regeneration, in which preexisting cardiomyocytes proliferate to replace the lost myocardium 1,2,3.
The growing interest in zebrafish research was paralleled by an increase in tools and methods. These phenomena indicate that h 2 o 2 may play a positive role in repair of aki. In contrast to mammals, zebrafish have the capacity to regenerate retinal neurons following a variety of injuries. By contrast, zebrafish are able to resolve the scar and to regenerate functional cardiac muscle. Zebrafish are able to efficiently regenerate lost cardiac muscle, and is used as a model to understand why natural heart regeneration is blocked in mammals. Renowned cardiologist helen taussig expressed concern in 1969 that it was not yet time for human trials, warning, our hope should be that physicians and surgeons will proceed with extreme caution until such time as a cardiac transplant will not announce the imminence of death but offer the patient the probability of a return to a useful life for a number of years. Kp split channel k,l,n,o or merged m,p confocal scans of dissociated. Review getting to the heart of regeneration in zebra.
In particular, our understanding of heart development has benefited greatly from zebrafish mutants that specifically disrupt cardiovascular form and function2931. It is not known how opposing cellular responses of fibrosis and new myocardium formation are spatially and temporally coordinated during heart regeneration in zebrafish. However, due to the lack of a suitable infarct model, it is not known how these animals respond to myocardial infarction. Specifically, we show that pololike kinase1 plk1 is an essential component of cardiomyocyte proliferation during heart regeneration. During heart regeneration in the zebrafish, fibrotic. Pdf advances in understanding the mechanism of zebrafish. Signals for cardiomyocyte proliferation during zebrafish.
Myocardial polyploidization creates a barrier to heart. Zebrafish, which any of you who are fish fans here, keep in the fish tank, can get to be about two inches long. Herein, we investigate the effect of h 2 o 2 in recovery of aki using zebrafish model inducing by gentamicin. Evidence for hormonal control of heart regenerative. Our data provides the first direct evidence for the source of proliferating cardiomyocytes during zebrafish heart regeneration and indicates that stemprogenitor cells are not significantly involved in this. Coronary artery disease accounts for the highest percentage of cvd deaths and stroke. Transient regenerative potential of the neonatal mouse heart. The underlying problem, in essence, is that up to a billion cardiomyocytes can be lost after myocardial infarction and that endogenous regeneration cannot restore the heart s function, resulting in increased risk for death by heart disease. Pdf in vivo cardiac reprogramming contributes to zebrafish. Regeneration of organs and appendages in zebrafish. Cardiac stem cell therapy and the promise of heart.
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