The zebrafish as a model of heart regeneration cloning. Zebrafish research may provide implications for heart regeneration in humans. Zebrafish as a smart model to understand regeneration. 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. Several models of myocardial infarction have been proposed in various mammalian organisms, including permanent ligation of the coronary artery or cryoinjury 1, 21, 22. Regenerating zebrafish hearts reveal the molecular agents of repair. Transient regenerative potential of the neonatal mouse heart. A heart attack occurs when blood flow to part of the heart is blocked, and oxygen and nutrients are unable to reach that tissue, irreversibly damaging cardiac muscle cells. Autophagy activation in zebrafish heart regeneration. This article is from journal of visualized experiments.
The adult human heart is an organ with low regenerative potential. The article is published in developmental cell this week. Using this system, we show here that regenerated heart muscle cells are derived from the. Here, we report that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and suppressed by estrogenantagonist tamoxifen. Injuries to the heart, but not other tissues, increased plasma. Regeneration, edited by catherina becker, thomas becker and joseph wu. Regeneration, plasticity, and induced molecular programs in adult zebrafish brain. Hematoxylin and eosin stain of the intact zebrafish heart before a and after about 20% ventricular resection b. The exact source of these new cardiomyocytes is a debated and unanswered question. While the zebrafish has emerged as a powerful model. After an initial blood clot forms to stanch the bleeding. Heart failure following acute myocardial infarction is a leading cause of death due to the inability of cardiomyocytes to proliferate and replenish lost cardiac muscle.
Mar 20, 2014 heart failure caused by cardiomyocyte loss after ischemic tissue damage is a leading cause of death worldwide. Zebrafish are native to river basins in and surrounding east india and were established as a laboratory model system first by streisinger and colleagues during the 1970s, as a potential means to apply genetic analysis to vertebrate development 1,2. The zebrafish as a model for complex tissue regeneration. Normal adult zebrafish can completely regenerate lost myocardium following partial amputation of the ventricle apex. Zebrafish heart regeneration developmental biology interactive. For instance, brdu labeling studies revealed labeled cardiomyocytes along the leading edge of the regenerating heart. Cardiac injury in mammals and amphibians typically leads to scarring, with minimal regeneration of heart muscle. Zebrafish therefore provide a model system in which to study how an injured heart can be repaired. Recently, it has been shown that adult zebrafish can also regenerate their hearts, thus offering new possibilities for experimentally approaching this fascinating biological phenomenon.
Unlike humans, zebrafish are able to completely repair their heart after injury, for example a myocardial infarctionlike event. Chla researchers discover a mechanism of heart regeneration. However, due to the lack of a suitable infarct model, it is not known how these animals respond to myocardial infarction. Zebrafish as a smart model to understand regeneration after heart. Furthermore, t lymphocytes are involved in the regeneration of several organs, such as spinal cord, heart and retina hui et al. The regenerative capacity of zebrafish reverses cardiac failure. Dec, 2002 cardiac injury in mammals and amphibians typically leads to scarring, with minimal regeneration of heart muscle. Pdf in vivo cardiac reprogramming contributes to zebrafish. Here, we found that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and is suppressed by the estrogenantagonist tamoxifen. Zebrafish as a model for studying cardiac regeneration. Unlike humans, zebrafish can regenerate their heart after injury, replacing the scarred tissue with new cardiomyocytes. Mapping of mitotic cms suggests epimorphic and compensatory mode of.
Studies uncover foundations of heart regeneration from. The cardiac endothelium has emerged as a key orchestrator of heart regeneration, influencing cardiomyocyte hyperplasia and tissue. In humans, myocardial infarction is characterized by irreversible loss of heart tissue, which becomes replaced with a fibrous scar. Here, we characterize the cellular response and regenerative capacity of the zebrafish heart after. Recent discoveries have advanced our understanding of how natural heart regeneration is regulated fig.
Nrp1 plays a key role in zebrafish heart regeneration, mediated through epicardial activation and migration and likely contributes to further physiological processes in other cardiac celltypes. However, to date, no study has been performed to elucidate zebrafish heart regeneration after a heart infarct. An inflammatory response precedes zebrafish brain regeneration kyritsis et al. Dead muscle cells are replaced by a noncontractile scar that affects cardiac function. Late developing cardiac lymphatic vasculature supports adult. Endothelial contributions to zebrafish heart regeneration. In contrast with adult mammals, zebrafish hearts show remarkable regenerative capabilities after substantial damage. 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. Injuries to the zebrafish heart, but not other tissues, increased plasma estrogen levels and the expression of estrogen receptors, especially esr2a. Fast revascularization of the injured area is essential to. First, developmental timing assays using transgenic reporters of contractile gene expression revealed that regeneration is initiated predominantly by. A dynamic epicardial injury response supports progenitor cell.
Here, we characterize the cellular response and regenerative capacity of the zebrafish heart after cryoinjury, an alternative procedure that. By contrast, teleost fish and urodele amphibians are capable of heart regeneration after a partial amputation. Scientists describe the mechanism of heart regeneration in. However, it is not yet known whether lymphatic vessels contribute to regeneration of zebrafish hearts. The cardiac endothelium has emerged as a key orchestrator of heart regeneration, influencing. 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. Myocardial infarction mi in humans is a common cause of cardiac injury and results in irreversible loss of myocardial cells and formation of. Researchers at the hubrecht institute have applied new tools to better understand how the zebrafish heart regenerates after injury. Regeneration occurs through robust proliferation of cardiomyocytes localized at the leading epicardial edge of the new myocardium. Shamoperated hearts and regenerating hearts were collected at 3, 7, and 14 dpa. Zebrafish heart regeneration occurs by cardiomyocyte. Zebrafish are extremely well suited to study organ regeneration.
Zebrafish are able to replace lost heart muscle efficiently, and are used as a model to understand why natural heart regeneration after. Chla researchers discover a mechanism of heart regeneration in zebrafish. Aug 08, 2019 thank you for submitting your article cardiac neural crest contributes to cardiomyocytes in amniotes and heart regeneration in zebrafish for consideration by elife. Apr 23, 2019 sexual differences are frequently observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clearly known.
The zebrafish has developed rapidly over the last 10 years as a model to study cardiac regeneration. Whether the capacity for cardiac regeneration is absent in mammals or whether it exists and is switched off early after birth has been unclear. Regeneration of ventricular myocardium in the resected zebrafish heart. In contrast to humans and other mammals, zebrafish hearts regenerate after substantial injury or tissue damage. Adult zebrafish possess a significant ability to regenerate injured heart tissue through proliferation of preexisting cardiomyocytes, which contrasts with the inability of mammals to do so after the immediate postnatal period. In particular, recent work has identified revascularization of the wound to be a sentinel event during heart regeneration. We report that 2,3,7,8tetrachlorodibenzopdioxin tcdd significantly impairs this regeneration. A dual epimorphic and compensatory mode of heart regeneration in zebrafish. A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Zebrafish heart regeneration developmental biology. Pdf advances in understanding the mechanism of zebrafish. Role of neuropilins in zebrafish heart regeneration ucl.
During heart regeneration in zebrafish, lost ventricular tissue is rapidly replaced. Unfortunately, the mammalian heart is unable to replace cardiomyocytes, so the life expectancy. Estrogen accelerates heart regeneration by promoting the. Myocardial polyploidization creates a barrier to heart. Gene expression analysis of zebrafish heart regeneration. Acute stress is detrimental to heart regeneration in zebrafish. Zebrafish may point the way to mending a broken heart. These cells migrate extensively during development to form many different parts of the body. Studies uncover foundations of heart regeneration from zebrafish. Abstractthe mammalian heart is incapable of significant regeneration following an acute injury. This zebrafish heart regeneration video is suitable for 9th 12th grade. Feb 25, 2011 certain fish and amphibians retain a robust capacity for cardiac regeneration throughout life, but the same is not true of the adult mammalian heart.
Oct 04, 2016 a heart attack occurs when blood flow to part of the heart is blocked, and oxygen and nutrients are unable to reach that tissue, irreversibly damaging cardiac muscle cells. After treatment with the mek inhibitor azd6244 upon cardiac injury, the core members in mapkerk signallingmek and erkdemonstrate elevated expression, and these proteins are deposited at the injury site in. Keatings theory is that while both regeneration and scarring are possible in the zebrafish, a competition takes place between the two. Sexual differences are frequently observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clearly known. Tcdd inhibits heart regeneration in adult zebrafish. 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. Mapkerk signalling is required for zebrafish cardiac.
Zebrafish heart regeneration is initiated by progenitor cells our experiments reveal several new mechanistic insights into zebrafish heart regeneration, from which we propose a model figure 7. The process of zebrafish heart regeneration after cryoinjury involves the initial phase of wound healing and cardiac blastema formation in the course of 14 days after injury, followed by the progressive replacement of fibrotic tissue with a new myocardium during the two subsequent weeks. But how is the fish able to regenerate this continued. Estrogen accelerates heart regeneration by promoting. Yap is required for scar formation but not myocyte. Zebrafish heart regeneration proceeds through injuryinduced proliferation of cardiomyocytes. To identify molecular signals that initiate regeneration, we focused our gene expression profile analysis on the early stages of zebrafish heart regeneration. Dynamics of zebrafish heart regeneration using an hplcesi. Transcriptomic analyses suggested heart injuries triggered more pronounced immune and. Ap1 contributes to chromatin accessibility to promote. Biologists discovered zebrafish have the ability to regenerate damaged hearts.
Pdf endothelial contributions to zebrafish heart regeneration. Jul 18, 2019 sexual differences are observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. Hyaluronic acid synthesis is required for zebrafish tail. New study on zebrafish may have possible relevance for. New study on zebrafish may have possible relevance for heart. In particular, our understanding of heart development has benefited greatly from zebrafish mutants that specifically disrupt cardiovascular form and function2931. A dynamic epicardial injury response supports progenitor. Before birth, unspecialized stem cells go through a process called differentiation to form the many types of cells found in the adult. Heart failure is a devastating disease, and one possible cure is to replace the lost cardiomyocytes through regeneration. Advances in understanding the mechanism of zebrafish heart. Zebrafish as a smart model to understand regeneration after. Notch signalling is required for zebrafish cardiac regeneration. After as little as 1 month, most of the missing tissue has been regenerated by cardiomyocytes. The adult mammalian heart is minimally regenerative after injury, whereas neonatal hearts fully recover even after major damage.
In this experimental paradigm, 20% of the zebrafish heart ventricle is surgically removed, and due to its cardiac regeneration capacity, tissue restoration is completed in about 4060 days 16. Thus, injuryinduced cardiomyocyte proliferation in zebrafish can overcome scar formation, allowing cardiac muscle regeneration. This article was downloaded from harvard universitys dash repository, and is. Here, we demonstrate histologically that zebrafish fully regenerate hearts within 2 months of 20% ventricular resection. Autophagic vesicle formation in the heart ventricle is increased during zebrafish cardiac regeneration.
Injuries to the heart, but not other tissues, increased plasma estrogen level and expression of estrogen. The zebrafish heart regenerates after cryoinjuryinduced. Because of this, scientists often study zebrafish to try to find ways to improve healing of heart injuries in humans. Nov 12, 2019 chla researchers discover a mechanism of heart regeneration in zebrafish. To better understand the molecular mechanisms of regeneration and explore the potential signalling pathways as therapeutic targets for heart attacks. In the zebrafish, injured tissue leads to development of a scar consisting of collagen and fibrin, which is ultimately replaced with new contractile muscle. Among these regenerative structures, the adult zebrafish tail is unparalleled for its accessibility to amputation and relatively simple cellular organization 4 6. The heart most often weakens through the loss of muscle cells, called cardiomyocytes. Oct 27, 2015 heart failure occurs when the heart cannot pump enough blood to meet the bodys demands.
To characterize protein dynamics during heart regeneration, we employed an hplcesimsms mass spectrometry approach. During zebrafish heart regeneration, the regenerating heart is sometimes said to become embryoniclike because genes normally expressed during heart development are found expressed in cells along the outer most layer of the heart, the epicardium lepilina et al. The asterisk marks a large blood clot adjacent to the left ventricular chamber arrow at 1 and 2 dpr. Mar 25, 2010 zebrafish are able to replace lost heart muscle efficiently, and are used as a model to understand why natural heart regeneration after a heart attack, for instance is blocked in mammals. We found that the hearts of 1dayold neonatal mice can regenerate after partial surgical resection. Neurotransmitterregulated regeneration in the zebrafish retina. Unlike humans, zebrafish can efficiently regenerate their hearts after injury.
In uninjured hearts cardiomyocytes are displayed in an ordered. Sexual differences are observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. How to regenerate a zebrafish heart hubrecht institute. Heart failure occurs when the heart cannot pump enough blood to meet the bodys demands. A images of a regenerating zebrafish ventricle following 20% ventricular resection.
Late developing cardiac lymphatic vasculature supports. An important mechanistic feature of zebrafish heart regeneration was revealed by recent genetic fatemapping experiments, which indicated that existing. 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. Migration of cardiomyocytes is essential for heart. The epicardium plays a crucial role in zebrafish heart regeneration,14.
Zebrafish heart regeneration as a model for cardiac tissue. Although this regeneration model has proved useful for the elucidation of certain regeneration mechanisms, it is based on the removal of heart tissue rather than its damage. The zebrafish as a model of heart regeneration cloning and. In the 2002 study, keatings group outlined the course of zebrafish heart regeneration.
This fibrotic tissue preserves the integrity of the ventricular wall but undermines pump function, leading to congestive heart failure. Histological characterization of the dicer1 mutant zebrafish retina. The zebrafish has emerged as a powerful model for studying regeneration of the heart, spinal cord, liver, pancreas, retina, tail, and other tissues 2,3. Nov 08, 2019 because of this, scientists often study zebrafish to try to find ways to improve healing of heart injuries in humans. Myocardial infarction mi in humans is a common cause of cardiac injury and results in irreversible loss of myocardial cells and formation of fibrotic scar tissue. Now, researchers in three recent publications have discovered mysterious properties of the epicardium that could help explain the fishs remarkable. Induction of myocardial infarction in adult zebrafish. Although adult mammalian cardiomyocytes are able to proliferate during normal aging and after infarction, they do so at insufficient rates for effective cardiac regeneration. 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. To determine which of these cellular events is more.
Neural crest cells are a group of these stem cells found in all animals with backbones i. Volume 127, issue 3, 3 november 2006, pages 607619. Cardiac neural crest contributes to cardiomyocytes in. Experiments were performed on abline adult zebrafish n40 in which 15% of the ventricle was surgically removed. Hector sancheziranzo et al, tbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration, nature communications 2018. 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. Gene expression profiling of zebrafish heart regeneration. Primary contribution to zebrafish heart regeneration by. However, it remains unknown what important processes cardiomyocytes. This study established a highresolution echocardiography for tissue doppler imaging tdi of the zebrafish heart to explore the cardiac functions during different regeneration phases. This is the first report of an injuryinduced epicardial activation phenotype caused by the disruption of a single allele in zebrafish.
Likewise, none of several described cardiac stem cell populations appear to form significant numbers of. Adult male zebrafish were injected with vehicle control or tcdd 70ngg, ip 1 day prior to partial amputation of the ventricle apex. A combination of forward genetic screens, large clutch size, and external development has made the zebrafish a popular model system for ontogenetic development. One of the most remarkable examples is heart regeneration ausoni and sartore, 2009.
Primordial, cortical, and trabecular muscles are defined in the zebrafish heart. Zebrafish heart regeneration video for 9th 12th grade. Signals for cardiomyocyte proliferation during zebrafish heart regeneration. Highresolution tissue doppler imaging of the zebrafish. Zebrafish find popularity among aquarium owners for their beauty and biologists for their unique abilities. After heart injury, zebrafish cardiomyocytes can divide and the scar is replaced by new. Extensive scar formation and regression during heart. The epicardium plays a crucial role in zebrafish heart regeneration,14, as epicardial markers such as tbx18, tcf21 and raldh2 are reexpressed after cryoinjury, suggesting that tissue injury. Unfortunately, the mammalian heart is unable to replace cardiomyocytes, so the. Autophagy activation in zebrafish heart regeneration scientific. Over the decades that have followed, zebrafish have become a valuable tool to dissect embryogenesis. Failure to properly repair damaged due to myocardial infarction is a major cause of heart failure.
Unlike humans, zebrafish can regenerate their heart after injury, replacing the scarred tissue with new. The zebrafish heart has the capacity to regenerate after ventricular resection. To directly address the source of newly formed cardiomyocytes during zebrafish heart regeneration, we first established a genetic strategy to lineagetrace cardiomyocytes in the adult fish, based on the crelox system widely used in the mouse6. Studies over the past two decades have shown heart regeneration in zebrafish to be a dynamic process, choreographed by multiple cell types. C an intact ventricular apex at higher magnification, indicating the approximate amputation plane dashed line.
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