At first sight, it seems natural to imagine that in tissues that are competent for regeneration, local signals provoked by injury, control the key regenerative events. Itou j, oishi i, kawakami h, glass tj, richter j, johnson a et al. Here, we present a protocol for induction of a heart infarct in adult zebrafish using cryoinjury. Now, researchers in three recent publications have discovered mysterious properties of the epicardium that could help explain the fishs remarkable. An increase in the expression of the cardiac progenitor associated genes nkx2. The zebrafish heart regenerates after cryoinjuryinduced. At its inception, the unprecedented work relied on an opportunity grant from the sandler foundation through the ucsf program for breakthrough biomedical research, which led to further support from. In this study we compared the regenerative outcomes of adult zebrafish exposed to one round of phototoxic treatment with adult zebrafish exposed to six consecutive rounds of. However, due to the lack of a suitable infarct model, it is not known how these animals respond to myocardial infarction. An important mechanistic feature of zebrafish heart regeneration was revealed by recent. May 15, 2012 zebrafish regenerate cardiac muscle after severe injuries through the activation and proliferation of spared cardiomyocytes. Hypoxiareoxygenation cardiac injury and regeneration in. Notch signalling is required for zebrafish cardiac regeneration.
Zebrafish heart regeneration developmental biology interactive. In humans, myocardial infarction is characterized by irreversible loss of heart tissue, which becomes replaced with a fibrous scar. Whereas inflammation appears to have an inhibitory effect on mammalian neural regeneration by. Migration of cardiomyocytes is essential for heart regeneration in.
However, evidence for the requirement of nerves during blastema formation in the zebrafish caudal fin is still missing. Regeneration occurs through robust proliferation of cardiomyocytes localized at the leading epicardial edge of the new myocardium. Dec, 2002 regeneration occurs through robust proliferation of cardiomyocytes localized at the leading epicardial edge of the new myocardium. The research reflects a new approach to modeling the possibilities for human regeneration using highly regenerative organisms like the zebrafish. From the university of pittsburgh, researchers applied extracellular matrices ecms from zebrafish in. New research could help humans experience the benefits of regeneration, using components from a zebrafish to regenerate damaged and dead heart tissue. Advances in understanding the mechanism of zebrafish heart.
However, no zebrafish model is available that mimics ischemic injury in mammalian heart. Zebrafish represents a valuable model to study the mechanisms of heart regeneration in vertebrates. The art of fin regeneration in zebrafish pfefferli 2015. Scientists describe the mechanism of heart regeneration in. Keatings theory is that while both regeneration and scarring are possible in the zebrafish, a competition takes place between the two. Zebrafish as a model for studying cardiac regeneration.
To address the extent to which cardiomyocytes dedifferentiate during zebrafish heart regeneration, regenerating hearts were analyzed using transmission electron microscopy tem of a control nonamputated heart fig 3. Although mitotic events have been observed in the initial study of zebrafish heart regeneration ahuja et al. Resolving heart regeneration by replacement histone. Compared with zebrafish, the medaka heart responded differently to an injury. Zebrafish regulatory t cells mediate organspecific. Regenerating hearts with zebrafish tissue cardiology. Quantification of mphase events is essential to determine a spatiotemporal. However, as noted, during heart regeneration in zebrafish the response is first initiated in an area including the injury site but also distant from the injury. Studies uncover foundations of heart regeneration from zebrafish. Reepithelialization of cutaneous wounds in adult mammals takes days to complete and relies on numerous signalling cues and multiple overlapping cellular processes that take place both within the epidermis and in other participating tissues. The zebrafish information network zfin is the database of genetic and genomic data for the zebrafish danio rerio as a model organism. The exact source of these new cardiomyocytes is a debated and unanswered question.
After as little as 1 month, most of the missing tissue has been regenerated by cardiomyocytes. The heart most often weakens through the loss of muscle cells, called cardiomyocytes. Hector sancheziranzo et al, tbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration, nature communications 2018. Here we investigated the extent to which mirnas regulate zebrafish heart regeneration. 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.
Normal anatomy and histology of the adult zebrafish. We developed and characterized zebrafish cardiac injury induced by hypoxiareoxygenation hr and the regeneration that followed it. Adult zebrafish possess a significant ability to regenerate injured heart tissue through. Primary contribution to zebrafish heart regeneration by. Cnic scientists describe the mechanism of heart regeneration. Aims the adult zebrafish heart regenerates spontaneously after injury and has been used to study the mechanisms of cardiac repair.
Heart failure occurs when the heart cannot pump enough blood to meet the bodys demands. Jun 20, 20 whereas inflammation appears to have an inhibitory effect on mammalian neural regeneration by promoting glial scar formation and limiting cell proliferation, survival and migration, it does not seem to play such negative effect during zebrafish brain regeneration. Pdf in vivo cardiac reprogramming contributes to zebrafish. Scientists at johns hopkins take a closer look at how. Using hypoxyprobe, a chemical reagent that can be used to visualize hypoxic cells, the authors showed that hypoxia, while ubiquitous in injured ventricular tissue. However, these little one to twoinch fish, natives of indias ganges river, are also helping biomedical researchers learn about how our hearts develop and functionand.
Studies uncover foundations of heart regeneration from. The mechanism of zebrafish heart regeneration is not understood. Unlike humans, zebrafish can efficiently regenerate their hearts after injury. Specific macrophage populations promote both cardiac scar. In contrast, zebrafish hearts regenerate even when up to 20% of the ventricle is amputated. An excessive fibrotic response occurred in the medaka heart, and existing cardiomyocytes or cardiac progenitor cells.
Department of cell biology, department of cardiology, howard hughes medical institute, harvard medical school, childrens hospital, 320 longwood avenue, boston, ma 02115, usa. Zebrafish may point the way to mending a broken heart. A recurrent topic in this blog is how the inflammatory response modulates the regenerative versus the nonregenerative output after an injury in different contexts. Migration of cardiomyocytes is essential for heart. In uninjured hearts cardiomyocytes are displayed in an ordered. Unlike humans, zebrafish hearts can fully regenerate after ventricular injuries, thereby providing a tractable model system to study endogenous heart regeneration 5, 6.
Deoxygenated venous blood enters the sinus venosus figures 5 and 6. Zebrafish heart regeneration process uab barcelona. To identify molecular signals that initiate regeneration, we focused our gene expression profile analysis on the early stages of zebrafish heart regeneration. Mar 25, 2010 during heart regeneration in zebrafish, lost ventricular tissue is rapidly replaced. Human gene prevents regeneration in zebrafish uc san. Therefore, elucidating mechanisms of zebrafish heart regeneration. In summary, our data indicate that a new genetic program emerges during heart regeneration, representing a near doubling in the number of h3. Recent studies have shown that the adult zebrafish heart, unlike the mammalian heart, exhibits the ability to fully regenerate within weeks after surgical removal of the ventricular apex, cryoinjury, and genetic cardiomyocyte ablation. Acute inflammation and zebrafish brain regeneration. A ventricle cryoinjury is represented in the model, but the scheme is aimed at. Thus, injuryinduced cardiomyocyte proliferation in zebrafish can overcome scar formation, allowing cardiac muscle regeneration. A model for heart development more than just pets covered with iridescent scales and black stripes, zebrafish danio rerio are popular in home aquariums. Infiltrating ztreg cells produce tissuespecific proregenerative factors that stimulate tissueresident precursor cell proliferation, revealing new cellular targets for increasing regenerative capacity in poorly regenerating species.
Human gene prevents regeneration in zebrafish 18 november 2015, by nicholas weiler normally, a zebra fish s amputated tail fin completely regrows within 15 days left but the human tumor. During heart regeneration in the zebrafish, fibrotic. Studies uncover foundations of heart regeneration from zebrafish may 8, 2015 while the human heart cannot heal itself, the zebrafish heart can easily replace cells lost by damage or disease. The wall of the sinus venosus is thin and is mainly composed of collagenous connective tissue. By contrast, zebrafish efficiently regenerate lost cardiac muscle, providing a model for understanding how natural heart regeneration may be blocked or enhanced 4,5. Cell migration during heart regeneration in zebrafish ncbi nih. Cnic scientists describe the mechanism of heart regeneration in the zebrafish unlike humans, the zebrafish is able to regenerate its heart after injury. Autophagy activation in zebrafish heart regeneration scientific. The art of fin regeneration in zebrafish pfefferli. Celltypespecific chromatin profiling can shed light on intrinsic genetic programs, but such analysis in regenerating tissues has technical challenges. Scientists at johns hopkins take a closer look at how zebrafish regenerate eye tissue findings may advance efforts to combat degenerative eye disease damage in humans image caption. Some of the genes expressed during the different stages within the heart are marked as is the pathways they are controlling.
Researchers at the hubrecht institute have applied new tools to better understand how the zebrafish heart regenerates after injury. Cell migration during heart regeneration in zebrafish. Mar 25, 2010 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. Zebrafish heart regeneration relies on the capacity of cardiomyocytes to proliferate upon injury.
Coronary artery disease accounts for the highest percentage of cvd deaths and stroke, cardiomyopathies. The zebrafish is a wellestablished animal model to decipher the genetics of cardiovascular development and disease of vertebrates. In the absence of lineagetracing technology applicable to adult zebrafish, the cellular origins of newly regenerated cardiac muscle have remained unclear. Although most studies of cardiac regeneration in vertebrates indicate that scarring is a major problem, the zebrafish continued to regenerate heart tissue with little or no scarring. 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. Although monitoring cells in adult zebrafish is still challenging for heart regeneration studies, an ex vivo whole heart culture wang et al. How to regenerate a zebrafish heart hubrecht institute.
They identify regulatory elements preferential for heart regeneration during the. But how is the fish able to regenerate this continued. Water and inhibitor or dmso alone were changed daily throughout the experimental procedures. In the zebrafish, the heart is situated anterior of the main body cavity and ventral to the esophagus poppe and ferguson 2006. Pdf macrophages directly contribute collagen to scar. Dec, 2002 the hearts of zebrafish with mutations in the mps1 mitotic checkpoint kinase, a critical cell cycle regulator, failed to regenerate and formed scars. Cardiac injury in mammals and amphibians typically leads to scarring, with minimal regeneration of heart muscle. This animation shows how zebrafish can rapidly heal wounds to the heart. Regeneration occurs through robust proliferation of. Zebrafish heart regeneration occurs by cardiomyocyte.
Recent studies have indicated that cardiomyocytes dedifferentiate in order to facilitate proliferation, yet it is unclear how far within the cardiac lineage they regress7, 8. Resolving heart regeneration by replacement histone profiling. Characterization of retinal regeneration in adult zebrafish. However, a damaged zebrafish heart can recover most of its original shape, size, and function over time. Little is known about factors that control these events. Differential reparative phenotypes between zebrafish and. Characterization of retinal regeneration in adult zebrafish following multiple rounds of phototoxic lesion alexandra h. Unlike humans, zebrafish are able to completely repair their heart after injury, for example a myocardial infarctionlike event. The ability of zebrafish to fully regenerate the adult heart was first reported by poss and colleagues in 2002. Complete tissue regeneration of multiple organs, including the heart, has been demonstrated in several vertebrate model systems such as the zebrafish. Belmonte and colleagues have recently addressed how the low oxygen condition, hypoxia, affects heart regeneration in zebrafish jopling et al.
Here, we demonstrate histologically that zebrafish fully regenerate hearts within 2 months of 20% ventricular resection. Stages of heart development in zebrafish embryos in a v. Scientists hope that by harnessing the ability to improve regeneration in zebrafish, they can better understand how to induce regeneration in human eyes, which. Induction of myocardial infarction in adult zebrafish. Pdf despite current treatment regimens, heart failure remains the leading cause of.
Aug 16, 2019 complete tissue regeneration of multiple organs, including the heart, has been demonstrated in several vertebrate model systems such as the zebrafish. Nov 17, 2015 the research reflects a new approach to modeling the possibilities for human regeneration using highly regenerative organisms like the zebrafish. Combining this approach with an ex vivo culture protocol to image epicardial regeneration. Reepithelialization of partial or fullthickness skin wounds of adult zebrafish, however, is extremely rapid and largely. Shamoperated hearts and regenerating hearts were collected at 3, 7, and 14 dpa. Regulation of zebrafish heart regeneration by mir3. F and fli1egfp signal, detected by antigfp antibody g, and a merged image h. Zebrafish hearts continue to beat normally after being removed and grown in the lab, perfect for a scientist studying their activity to make regeneration possible for humans. Schematic illustration of the main steps leading to cardiac regeneration in the zebrafish. Besides their electrophysiological functions in the heart, recent findings have demonstrated that ion channels also feature ion flux independent functions during heart development and morphogenesis. The regenerative capacity of zebrafish reverses cardiac failure.
Gene expression analysis of zebrafish heart regeneration. Zebrafish has a twochamber heart constituted by an atrium, a ventricle and a single coronary artery. By contrast, teleost fish and urodele amphibians are capable of heart regeneration after a partial amputation. During embryogenesis, the epicardium migrates out as a sheet from the proepicardium, a cluster or mesodermderived cells near the liver primordium and the septum transversum, to envelop the developing myocardial tube 43. When the human heart is severely wounded during, for example, a heart attack it cannot regenerate the damaged muscle tissue. A dual epimorphic and compensatory mode of heart regeneration. Zebrafish regenerate cardiac muscle after severe injuries through the activation and proliferation of spared cardiomyocytes. Cardiovascular disease cvd is one of the leading causes of death worldwide. Here we investigated the extent to which mirnas regulate zebrafish heart. The role of the epicardium during zebrafish heart regeneration recent results have shed light on the role of the outer nonmuscle layer of the heart, the epicardium, in cardiac regeneration. This method results in massive cell death within 20% of the ventricular wall, similar to that observed in mammalian infarcts. To systematically characterize this process at the molecular level, we generated transcriptional profiles of zebrafish cardiac regeneration by microarray analyses. The article is published in developmental cell this week. Among vertebrates, zebrafish are remarkable animals as they can regenerate their brains.
Cahill 1,3,4,10, amy kenyon 2, daria gavriouchkina 2,9. Oct 27, 2015 heart failure occurs when the heart cannot pump enough blood to meet the bodys demands. However, another teleost animal model, the medaka, had not yet been investigated for this capacity. Migration of cardiomyocytes is essential for heart regeneration in zebrafish. Coronary artery disease accounts for the highest percentage of cvd. Recent discoveries have advanced our understanding of how natural heart regeneration is regulated fig. To understand the principles of this process after cryoinjuryinduced myocardial infarction, we established a spatiotemporal map of mitotic cardiomyocytes and their differentiation dynamics. Heart failure is a devastating disease, and one possible cure is to replace the lost cardiomyocytes through regeneration. Gene expression profiling of zebrafish heart regeneration. In the amputation injury model about 20% of the apex is surgically removed. In 2015, duke scientists being working with their zebrafish heart explant culture system to study the epicardium, the outer layer of tissue covering the surface of. Zebrafish heart regeneration developmental biology.
Technical advancements in the future would likely provide direct analyses of cell. Human gene prevents regeneration in zebrafish uc san francisco. Zebrafish heart regeneration as a model for cardiac tissue. Primary contribution to zebrafish heart regeneration by gata4. Teleosts, as urodele amphibians, have the remarkable capacity to regenerate several organs and structures of their body after an injury. The hearts of zebrafish with mutations in the mps1 mitotic checkpoint kinase, a critical cell cycle regulator, failed to regenerate and formed scars. Cellular grownups outperform stem cells in cardiac repair.
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