Regulation of zebrafish heart regeneration by mir3. Here, we characterize the cellular response and regenerative capacity of the zebrafish heart after cryoinjury, an alternative procedure that. 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. Shamoperated hearts and regenerating hearts were collected at. The zebrafish heart has the capacity to regenerate after ventricular resection. Failure to properly repair damaged due to myocardial infarction is a major cause of heart failure.
In particular, the high ability to regenerate a variety of organs has made the zebrafish a suitable animal model for organ. 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 of heart regeneration cloning. In this study, we adapted the cryoinjury method to induce a heart infarct in zebrafish, because of the coronary vasculature is. A metabolic shift to glycolysis promotes zebrafish tail. Nonetheless, the genetic and cellular determinants of natural cardiac regeneration remain incompletely characterized. The zebrafish has developed rapidly over the last 10 years as a model to study cardiac regeneration. For more than a decade, zebrafish heart regeneration was studied exclusively using ventricular resection as the injury model fig. Nrg1 is an injuryinduced cardiomyocyte mitogen for the.
This fibrotic tissue preserves the integrity of the ventricular wall but undermines pump function, leading to congestive heart failure. Decellularized mammalian ecm has been extensively investigated in tissue engineering and regenerative medicine 25, 26. 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. The national heart lung and blood institute recently awarded wang a grant for this research. To identify molecular signals that initiate regeneration, we focused our gene expression profile analysis on the early stages of zebrafish heart regeneration. Primary contribution to zebrafish heart regeneration by. Over the decades that have followed, zebrafish have become a valuable tool to dissect embryogenesis. In zebrafish embryos, tail amputation through the posterior trunk of the animal results in repositioning of notochord cells to the amputation site, followed by blastema formation and regeneration of several different tissues including the. Burns acardiovascular research center, department of medicine, massachusetts general hospital and harvard medical school. Myocardium tissues were taken from shamoperated fish. Also, a wide array of molecular and genetic tools, including mutagenesis screens and complete genome sequence information, are available to those working with zebrafish.
A combination of forward genetic screens, large clutch size, and external development has made the zebrafish a popular model system for ontogenetic development. Data acquisition using hdms e demonstrates utility for experiments. 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 2. Injuries to the zebrafish heart, but not other tissues, increased plasma estrogen levels and the expression of estrogen receptors, especially esr2a.
Endothelial contributions to zebrafish heart regeneration. 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. In zebrafish embryos, tail amputation through the posterior trunk of the animal results in repositioning of notochord cells to the amputation site, followed by blastema formation and regeneration of. Scientists describe the mechanism of heart regeneration in. After as little as 1 month, most of the missing tissue has been regenerated by cardiomyocytes. Fast revascularization of the injured area is essential to. May 2017 720006008en ag pdf conclusions a multiomic study using labelfree strategies has been applied to the study of zebrafish to understand the biological processes involved in heart tissue regeneration post amputation. The animation illustrates the steps in this regeneration process, highlighting the role of cell signaling proteins called fibroblast growth factors fgf. 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. C an intact ventricular apex at higher magnification, indicating the approximate amputation plane dashed line.
Herein, we conducted a systematical search in embase and pubmed for studies on heart regeneration in the zebrafish following injury and identified 47 ar studies meeting the inclusion criteria. 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. Myocardial polyploidization creates a barrier to heart. Heart regeneration in amphibia and fish unlike humans, many amphibia and fish readily regenerate limbs, appendages and internal organs after injury. A combination of forward genetic screens, large clutch size and external development has made the zebrafish a popular model system for ontogenetic development. The exact source of these new cardiomyocytes is a debated and unanswered question.
Zebrafish heart regeneration proceeds through injuryinduced proliferation of cardiomyocytes. Telomerase is essential for zebrafish heart regeneration. But a systematic overview of the methods used to evidence heart regrowth and regeneration in the zebrafish is lacking. Zebrafish heart regeneration process uab barcelona. Here, we characterize the cellular response and regenerative capacity of the zebrafish heart after. 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.
Here, we report that cardiac regeneration in zebrafish relies on notch signaling. An increase in the expression of the cardiac progenitor associated genes nkx2. Injuries to the heart, but not other tissues, increased plasma. Chla researchers discover a mechanism of heart regeneration. Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration long zhaoa, asya l. Zebrafish embryos are particularly wellsuited to investigating the mysteries of heart disorders, because even embryos that develop severely malformed, nonbeating hearts can survive and continue to grow for several days.
Advances in understanding the mechanism of zebrafish heart. To characterize protein dynamics during heart regeneration, we employed an hplcesimsms mass spectrometry approach. Zebrafish heart regeneration occurs by cardiomyocyte. Extensive scar formation and regression during heart. Mar 25, 2010 during heart regeneration in zebrafish, lost ventricular tissue is rapidly replaced. He is also investigating the regeneration of coronary blood vessels. Genetic lineage tracing studies recently revealed that existing cms, not stem cells, are the major source of regenerating cardiac muscle in zebrafish jopling et al. Lifelong preservation of the regenerative capacity in the. Pdf endothelial contributions to zebrafish heart regeneration. Zebrafish models of cardiovascular disease springerlink. Chla researchers discover a mechanism of heart regeneration in zebrafish. Dec, 2002 zebrafish restore the ventricular myocardial wall, whereas published findings indicate little or no cardiac muscle regeneration after amphibian heart resection. Nov 12, 2019 chla researchers discover a mechanism of heart regeneration in zebrafish. Zebrafish heart regeneration as a model for cardiac tissue repair.
Neonatal mouse heart regeneration is similar to zebrafish heart regeneration, involving cardiomyocyte dedifferentiation and proliferation. More recently, wang has developed a system for culturing zebrafish hearts outside the body for one month. Unlike humans, zebrafish can regenerate their heart after injury, replacing the scarred tissue with new. Pdf advances in understanding the mechanism of zebrafish. Recently, it has been shown that adult zebrafish can also regenerate their hearts, thus offering new possibilities for experimentally approaching this fascinating biological phenomenon.
Studies over the past two decades have shown heart regeneration in zebrafish to be a dynamic process, choreographed by multiple cell types. Hematoxylin and eosin stain of the intact zebrafish heart before a and after about 20% ventricular resection b. However, it had not been known until recently whether these brdupositive cardiomyocytes result from proliferation of differentiated. However, a damaged zebrafish heart can recover most of its original shape, size, and function over time. Dynamics of zebrafish heart regeneration using an hplcesi. Zebrafish, regeneration, aging, heart, fin introduction the zebrafish has become a popular model animal to examine a variety of biological processes lieschke and currie, 2007. Nov 08, 2019 because of this, scientists often study zebrafish to try to find ways to improve healing of heart injuries in humans. Tcdd inhibits heart regeneration in adult zebrafish. Late developing cardiac lymphatic vasculature supports adult. 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 estrogen level and expression of estrogen. Using a proteomics approach, the authors found that the production. Analysis of the dynamic coexpression network of heart. To enable systematic insights into this phenomenon, we generated and integrated a dynamic coexpression network of heart regeneration in the zebrafish and linked systemslevel properties to the underlying molecular events.
Notch signaling regulates cardiomyocyte proliferation. The adult mammalian heart is minimally regenerative after injury, whereas neonatal hearts fully recover even after major damage. Primary contribution to zebrafish heart regeneration by gata4. Zebrafish heart regeneration developmental biology. Coronary artery disease accounts for the highest percentage of cvd. Unlike humans, zebrafish can regenerate their heart after injury, replacing the scarred tissue with new cardiomyocytes. Estrogen accelerates heart regeneration by promoting. Thats much longer than any other in vitro culture system. Dynamics of zebrafish heart regeneration using an hplcesims.
In this injury paradigm, a portion of the ventricle is removed, and regeneration is scored as complete regrowth of the lost tissue poss et al. It remains unclear why certain nonmammalian species efficiently regenerate their hearts while mammals fail in this endeavor. Recent discoveries have advanced our understanding of how natural heart regeneration is regulated fig. Teleosts, as urodele amphibians, have the remarkable capacity to regenerate several organs and structures of their body after an injury. 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. In contrast with adult mammals, zebrafish hearts show remarkable regenerative capabilities after substantial damage. Coronary artery disease accounts for the highest percentage of cvd deaths and stroke, cardiomyopathies. A multiomic approach for the study of heart regeneration. In particular, our understanding of heart development has benefited greatly from zebrafish mutants that specifically disrupt cardiovascular form and function2931. Gene expression analysis of zebrafish heart regeneration chingling lien1,2a, michael schebesta1,2, shinji makino1,2, gerhard j. Shamoperated hearts and regenerating hearts were collected at 3, 7, and 14 dpa. Hector sancheziranzo et al, tbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration, nature communications 2018. The zebrafish as a model for complex tissue regeneration.
Review hefssa heart failure society of south africa. 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. Cardiovascular disease cvd is one of the leading causes of death worldwide. Mammalian cardiac ecm has reportedly been beneficial when administered to the ischemic heart 27, 28. The zebrafish as a model of heart regeneration cloning and. Migration of cardiomyocytes is essential for heart. Aug 17, 2017 for more than a decade, zebrafish heart regeneration was studied exclusively using ventricular resection as the injury model fig. Nrg1 is an injuryinduced cardiomyocyte mitogen for the endogenous heart regeneration program in zebrafish matthew gemberling, ravi karra, amy l dickson, kenneth d poss department of cell biology, howard hughes medical institute, duke university medical center, durham, united states.
Jul 18, 2019 sexual differences are observed in the onset and prognosis of human cardiovascular diseases, but the underlying mechanisms are not clear. Gene expression analysis of zebrafish heart regeneration. The ability of zebrafish to fully regenerate the adult heart was first reported by poss and colleagues in 2002. Several models of myocardial infarction have been proposed in various mammalian organisms, including permanent ligation of the coronary artery or cryoinjury 1,21,22. As in regeneration of many different mammalian organs, the core issues in cardiac regeneration remain mysterious, and we have yet to understand what signals start the regenerative process, how regeneration is guided, and finally, how regeneration is terminated. Borikovaa, raz benyaira, burcu guneratamana, calum a. In particular, recent work has identified revascularization of the wound to be a sentinel event during heart regeneration. Because of the embryos small size, it does not need a working heart. Cardiac stem cell therapy and the promise of heart. Decellularized zebrafish cardiac extracellular matrix. In contrast to humans and other mammals, zebrafish hearts regenerate after substantial injury or tissue damage. Zebrafish as a model for studying cardiac regeneration. Here, we found that zebrafish heart regeneration is faster in females, can be accelerated by estrogen and is suppressed by the estrogenantagonist tamoxifen.
Estrogen accelerates heart regeneration by promoting the. 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. However, it is not yet known whether lymphatic vessels contribute to regeneration of zebrafish hearts. Unfortunately, the mammalian heart is unable to replace cardiomyocytes, so the. Keating1,2b 1 department of cardiology, childrens hospital, boston, massachusetts, united states of america, 2 department of cell biology, harvard medical school, boston. Primary contribution to zebrafish heart regeneration by gata4 1 cardiomyocytes kazu kikuchi 1,2, jennifer e. Thus, dissecting successful heart regeneration in zebrafish can provide context for understanding, and possibly enhancing, mammalian cardiac regenerative capacity. 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. Dead muscle cells are replaced by a noncontractile scar that affects cardiac function. Ventricular amputation was performed as previously published raya et al. For instance, brdu labeling studies revealed labeled cardiomyocytes along the leading edge of the regenerating heart. Now, researchers in three recent publications have discovered mysterious properties of the epicardium that could help explain the fishs remarkable.
Cells free fulltext a systematic exposition of methods. Zebrafish as a smart model to understand regeneration. The cardiac endothelium has emerged as a key orchestrator of heart regeneration, influencing. 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. During heart regeneration in zebrafish, lost ventricular tissue is rapidly replaced.
Gene expression profiling of zebrafish heart regeneration. Zebrafish heart regeneration as a model for cardiac tissue. Studies uncover foundations of heart regeneration from zebrafish. Notch signaling regulates cardiomyocyte proliferation during. There is a long history of research on amphibian heart regeneration9. 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. Therefore, regeneration of the urodele heart may be accomplished, at least partially, through dedifferentiation events.
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