Prrx1b restricts fibrosis and promotes Nrg1-dependent cardiomyocyte proliferation during zebrafish heart regeneration
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE153170 | GEO | 2021/09/16
REPOSITORIES: GEO
Similar Datasets
Project description:By contrast with mammals, adult zebrafish have a high capacity to regenerate damaged or lost myocardium through proliferation of spared cardiomyocytes. The epicardial sheet covering the heart is activated by injury and aids muscle regeneration through paracrine effects and as a multipotent cell source, and has received recent attention as a target in cardiac repair strategies. While it is recognized that epicardium is required for muscle regeneration and itself has high regenerative potential, the extent of cellular heterogeneity within epicardial tissue is largely unexplored. In this study, we performed transcriptome analysis on dozens of epicardial lineage cells purified from zebrafish harboring a transgenic reporter for the pan-epicardial gene tcf21. Hierarchical clustering analysis suggested the presence of at least three epicardial cell subsets defined by expression signatures. We validated many new pan-epicardial and epicardial markers by alternative expression assays. Additionally, we explored the function of the scaffolding protein and main component of caveolae, caveolin-1 (cav1), which was present in each epicardial subset. In BAC transgenic zebrafish, cav1 regulatory sequences drove strong expression in ostensibly all epicardial cells and in coronary vascular endothelial cells. Moreover, cav1 mutant zebrafish generated by genome editing showed grossly normal heart development and adult cardiac anatomy, but displayed profound defects in injury-induced cardiomyocyte proliferation and heart regeneration. Our study defines a new platform for the discovery of epicardial lineage markers, genetic tools, and mechanisms of heart regeneration. Deep sequencing of isolated single epicardial cells
2015-12-15 | E-GEOD-75583 | biostudies-arrayexpress
Project description:Ischemic cardiopathy is the leading cause of death in the world, for which efficient regenerative therapy is not currently available. In mammals, after a myocardial infarction episode, the damaged myocardium is replaced by scar tissue featuring collagen deposition and tissue remodelling with negligible cardiomyocyte proliferation. Zebrafish, in contrast, display an extensive regenerative capacity as they are able to restore completely lost cardiac tissue after partial ventricular amputation. Due to the lack of genetic lineage tracing evidence, it is not yet clear if new cardiomyocytes arise from existing contractile cells or from an uncharacterised set of progenitors cells. Nonetheless, several genes and molecules have been shown to participate in this process, some of them being cardiomyocyte mitogens in vitro. Though questions as what are the early signals that drive the regenerative response and what is the relative role of each cardiac cell in this process still need to be answered, the zebrafish is emerging as a very valuable tool to understand heart regeneration and devise strategies that may be of potential value to treat human cardiac disease. Here, we performed a genome-wide transcriptome profile analysis focusing on the early time points of zebrafish heart regeneration and compared our results with those of previously published data. Our analyses confirmed the differential expression of several transcripts, and identified additional genes the expression of which is differentially regulated during zebrafish heart regeneration. We validated the microarray data by conventional and/or quantitative RT-PCR. For a subset of these genes, their expression pattern was analyzed by in situ hybridization and shown to be upregulated in the regenerating area of the heart. The specific role of these new transcripts during zebrafish heart regeneration was further investigated ex vivo using primary cultures of zebrafish cardiomyocytes and/or epicardial cells. Our results offer new insights into the biology of heart regeneration in the zebrafish and, together with future experiments in mammals, may be of potential interest for clinical applications. In order to study zebrafish heart regeneration, a time course experiment was realized where amputated heart regenerating were compared to control heart. Samples in triplicate were extracted at 1, 3, 5 and 7 days post-amputation.
2010-03-09 | E-GEOD-17993 | biostudies-arrayexpress
Project description:By contrast with mammals, adult zebrafish have a high capacity to regenerate damaged or lost myocardium through proliferation of spared cardiomyocytes. The epicardial sheet covering the heart is activated by injury and aids muscle regeneration through paracrine effects and as a multipotent cell source, and has received recent attention as a target in cardiac repair strategies. While it is recognized that epicardium is required for muscle regeneration and itself has high regenerative potential, the extent of cellular heterogeneity within epicardial tissue is largely unexplored. In this study, we performed transcriptome analysis on dozens of epicardial lineage cells purified from zebrafish harboring a transgenic reporter for the pan-epicardial gene tcf21. Hierarchical clustering analysis suggested the presence of at least three epicardial cell subsets defined by expression signatures. We validated many new pan-epicardial and epicardial markers by alternative expression assays. Additionally, we explored the function of the scaffolding protein and main component of caveolae, caveolin-1 (cav1), which was present in each epicardial subset. In BAC transgenic zebrafish, cav1 regulatory sequences drove strong expression in ostensibly all epicardial cells and in coronary vascular endothelial cells. Moreover, cav1 mutant zebrafish generated by genome editing showed grossly normal heart development and adult cardiac anatomy, but displayed profound defects in injury-induced cardiomyocyte proliferation and heart regeneration. Our study defines a new platform for the discovery of epicardial lineage markers, genetic tools, and mechanisms of heart regeneration.
2015-12-15 | GSE75583 | GEO
Project description:The epicardium, a thin mesothelial tissue layer that encompasses the heart, is a dynamic structure that is essential for cardiac regeneration in species with elevated regenerative capacity like zebrafish. To dissect epicardial cell states and associated pro-regenerative functions, we performed single-cell RNA-sequencing and identified 7 epicardial cell clusters in adult zebrafish, with 3 of these clusters enhanced during regeneration. ECM components encoded by hapln1 paralogs label an enriched epicardial cell type that accumulates and encloses dedifferentiated and proliferating cardiomyocytes during regeneration. Genetic inactivation of hapln1b, or induced genetic depletion of hapln1a-expressing cells, disrupted cardiomyocyte proliferation and heart regeneration. hapln1a+ cells first emerge at the juvenile stage, when they associate with and are required for cardiogenic foci that direct growth of the juvenile heart. Our findings identify a subset of epicardial cells that emerges in post-embryonic animals and sponsors regions of active cardiomyogenesis during heart growth and regeneration
2022-06-17 | GSE172511 | GEO
Project description:Cardiovascular disease is the leading cause of morbidity and mortality in the Western world due to a limited regenerative capacity. In lieu of new muscle synthesis, the human heart replaces necrotic tissue with deposition of a non-contractile scar. In contrast, the adult zebrafish is endowed with a remarkable regenerative capacity, capable of de novo cardiomyocyte (CM) creation and scar tissue resolution when challenged with an acute injury. In these studies, we examined the contributions of the dynamically regulated microRNA, miR-101a, during adult zebrafish heart regeneration. We demonstrate that miR-101a expression is rapidly depleted within 3 days post-amputation (dpa) but is highly upregulated by 7-14 dpa, before returning to uninjured levels at the completion of the regenerative process. Employing heat-inducible transgenic strains and antisense oligonucleotides, we demonstrate that decreases in miR-101a levels at the onset of cardiac injury enhanced CM proliferation. Interestingly, prolonged suppression of miR-101a activity stimulates new muscle synthesis but with defects in scar tissue resolution. Upregulation of miR-101a expression between 7-14 dpa is critical to stimulate remodeling of the scar. Through a series of studies, we identified the proto-oncogene, fosab (cfos) as a potent miR-101a target gene, stimulator of CM proliferation, and inhibitor of scar tissue remodeling. Importantly, combinatorial depletion of fosab and miR-101a activity rescued defects in scar tissue resolution mediated by miR-101a inhibition alone. In summation, our studies indicate that the precise temporal modulation in the miR-101a/fosab genetic axis is critical for coordinating CM proliferation and scar tissue resolution during zebrafish heart regeneration. Pooled cardiac samples from uninjured and regenerating (6hpa) adult fish in biological triplicate.
2015-11-05 | E-GEOD-74494 | biostudies-arrayexpress
Project description:Unlike the adult mammalian heart, which has limited regenerative capacity, the zebrafish heart can fully regenerate following injury. Reactivation of cardiac developmental programmes is considered key to successfully regenerating the heart, yet the regulatory elements underlying the response triggered upon injury and during development remain elusive. Organ-wide activation of the epicardium is essential for zebrafish heart regeneration and is considered a potential regenerative source to target in the mammalian heart. Here we compared the transcriptome and epigenome of the developing and regenerating zebrafish epicardium by integrating gene expression profiles with open chromatin ATAC-seq data. We identified epicardial enhancer elements with specific activity during development or during adult heart regeneration. By generating gene regulatory networks associated with epicardial development and regeneration, we inferred genetic programmes driving each of these processes, which were largely distinct. We identified Wt1a, Wt1b, and the AP-1 subunits Junbb, Fosab and Fosb as central regulators of the developing network, whereas Hif1ab, Nrf1, Tbx2b and Zbtb7a featured as putative central regulators of the regenerating epicardial network. Targeting hif1ab, nrf1, tbx2b and zbtb7a using CRISPR/Cas9 in injured hearts resulted in elevated epicardial cell numbers infiltrating the wound and excess fibrosis after cryoinjury, illustrating the functional importance of these regulatory factors during zebrafish heart regeneration. Our work reveals striking differences between the regulatory blueprint deployed during epicardial development and regeneration. These findings underline that heart regeneration goes beyond the reactivation of developmental programmes and provide important insights into epicardial regulation.
2023-12-01 | GSE178751 | GEO
Project description:Adult zebrafish regenerate heart muscle after severe cardiac damage without significant scarring. The epicardium, a mesothelial cell sheet covering the vetebrate heart, is activated by injury and supports muscle regeneration through paracrine effects and as a source of multipotent cells. The understudied cellular heterogeneity of the adult epicardium during heart regeneration has constrained the effort in mobilizing the epicardium for heart repair. To dissect epicardial cell states and the underlying mechanisms that lead to successful heart regeneration in zebrafish, we performed single-cell RNA-sequencing of isolated epicardial cells from the regenerating adult heart and revealed their dynamic cellular heterogeneity. We defined the epithelial and mesenchymal layers of the epicardium and identified a transiently activated epicardial progenitor cell (aEPC) subpopulation that expresses aldh1a2, ptx3a, col12a1b and marcksb. Upon heart amputation injury, aEPCs emerge from the existing epicardial cells, migrate to enclose the wound, and disappear as regeneration progresses. Genetic lineage tracing combined with modified RNA labelling confirmed an epithelial-mesenchymal transition (EMT) process of aEPCs and their differentiations to pdgfrb+ mural cells and pdgfra+hapln1a+ mesenchymal fibroblast-like cells that support heart regeneration. Genetic ablation of aEPCs blocked wound closure of the injured ventricle, suppressed cardiomyocyte proliferation, and disrupted heart regeneration. Our findings define a transient progenitor state of the adult epicardium that is an indispensable driver of zebrafish heart regeneration and identified ptx3a as a regeneration-specific non-ontogenetic regulator of the epicardium.
2022-11-22 | GSE202836 | GEO
Project description:Ischemic cardiopathy is the leading cause of death in the world, for which efficient regenerative therapy is not currently available. In mammals, after a myocardial infarction episode, the damaged myocardium is replaced by scar tissue featuring collagen deposition and tissue remodelling with negligible cardiomyocyte proliferation. Zebrafish, in contrast, display an extensive regenerative capacity as they are able to restore completely lost cardiac tissue after partial ventricular amputation. Due to the lack of genetic lineage tracing evidence, it is not yet clear if new cardiomyocytes arise from existing contractile cells or from an uncharacterised set of progenitors cells. Nonetheless, several genes and molecules have been shown to participate in this process, some of them being cardiomyocyte mitogens in vitro. Though questions as what are the early signals that drive the regenerative response and what is the relative role of each cardiac cell in this process still need to be answered, the zebrafish is emerging as a very valuable tool to understand heart regeneration and devise strategies that may be of potential value to treat human cardiac disease. Here, we performed a genome-wide transcriptome profile analysis focusing on the early time points of zebrafish heart regeneration and compared our results with those of previously published data. Our analyses confirmed the differential expression of several transcripts, and identified additional genes the expression of which is differentially regulated during zebrafish heart regeneration. We validated the microarray data by conventional and/or quantitative RT-PCR. For a subset of these genes, their expression pattern was analyzed by in situ hybridization and shown to be upregulated in the regenerating area of the heart. The specific role of these new transcripts during zebrafish heart regeneration was further investigated ex vivo using primary cultures of zebrafish cardiomyocytes and/or epicardial cells. Our results offer new insights into the biology of heart regeneration in the zebrafish and, together with future experiments in mammals, may be of potential interest for clinical applications.
2010-02-25 | GSE17993 | GEO
Project description:Heart failure results from the inability of the human heart to replenish damaged tissue after myocardial infarction (MI), forming an unresolved scar which leads to functional impairment and tissue remodeling. Unlike humans, many animals, including certain fish and amphibians, are able to regenerate their hearts. Comparative analyses have been performed in many model systems including zebrafish (Danio rerio), with the goal to identify factors that could promote cardiac regeneration in humans. However, profound physiological differences between regenerative and non-regenerative models often make it difficult to extract informative data that are directly relevant to cardiac regeneration. Recently, medaka (Oryzias latipes), another fresh water teleost, has been reported to lack activation of neovascularization and cardiomyocyte (CM) proliferation post cardiac injury, and to display excessive fibrosis and an unresolved scar. This finding constitutes a unique opportunity to directly compare reparative responses to cardiac injury between regenerative (zebrafish) and non-regenerative (medaka) models with common physiological condition and anatomical structures, as well as phylogenetically close orthologous genes. Here we investigate potential triggers that promote heart regeneration using a comparative transcriptomic analysis between zebrafish and medaka. We generated a detailed dataset containing more than 15000 orthologous genes, covering multiple time points in the first week after cardiac injury. Analyses based on gene ontology revealed that differential responses in processes such as the immune response and angiogenesis exist between the two models. Pathway analyses further suggested potential candidates accounting for these differential responses including the Toll-like receptor agonist poly I:C. Altogether, these data provide further insight into the complex role of the immune response during regeneration, and serve as a platform to identify and test additional regulators of cardiac repair.
2017-06-20 | GSE94617 | GEO
Project description:Canonical roles for macrophages in mediating the fibrotic response after a heart attack (myocardial infarction) include turnover of the extracellular matrix and activation of cardiac fibroblasts to initiate collagen deposition. Here we reveal through studying the functional kinetics of fibrosis during zebrafish heart regeneration and mouse heart repair that macrophages can directly contribute collagen to the forming scar. Unbiased transcriptomics revealed an up-regulation of collagen isoforms in both zebrafish and mouse macrophages following injury. Adoptive transfer of macrophages from collagen-tagged transgenic zebrafish and splenic monocyte-derived macrophages from adult mouse GFPtpz-collagen donors, enhanced scar formation and induced fibrosis, respectively, via cell autonomous production of collagen. In zebrafish, macrophage-specific targeting of collagen 4a binding protein and cognate collagen 4a1 followed by transfer led to significantly reduced scarring in cryo-injured hosts. These findings contrast with the current model of scarring whereby collagen deposition is exclusively attributed to myofibroblasts, and implicate macrophages as direct contributors to fibrosis during heart repair.
2019-12-18 | GSE100029 | GEO