Midkine-a regulates the formation of a fibrotic scar during zebrafish heart regeneration
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PROVIDER: PRJNA701763 | ENA |
REPOSITORIES: ENA
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Project description:Midkine-a is a cytokine that is highly expressed in the heart upon injury that its role in regeneration has not been identified. We generated a KO zebrafish lines, mdkacn105, and studied the effect of mdka deletion in zebrafish adult heart regeneration. By combining histology and high-throughput genomics, we found that loss of mdka leads to arrest of heart regeneration. Mdka mutant hearts display increased collagen deposition in the site of the injury and decreased proliferation of the coronary endothelial cells due to increased expression of ECM including collagen and periostin as well as decreased expression of Hif1a. Our results demonstrate the importance of a balanced fibrotic respond is necessary for heart regeneration and indicates mdka importance in this process.
2021-05-26 | GSE166732 | 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
Project description:The adult mammalian heart heals after myocardial infarction (MI) by deposition of scar tissue, leading to downstream arrhythmia, remodelling and heart failure1. In contrast, adult zebrafish and neonatal mouse hearts are capable of regenerating after injury. Macrophages are key mediators of tissue repair and appear to be required for both regeneration and healing by scar formation, but the mechanisms underlying these distinct roles are poorly understood2-4. Here we investigated how macrophages differentially influence the mode of repair by determining their responses in scar-free versus scar-induced healing, comparing ventricular resection with cryo-injured adult zebrafish hearts and neonatal versus adult mouse hearts after MI. Unbiased transcriptomics revealed molecular programmes implicating macrophages in the initiation and resolution of inflammation to dictate the kinetics of scarring during zebrafish regeneration and the activation of direct and indirect pathways to drive fibrosis in the adult mouse heart. Most notably we observed up-regulation of collagen isoforms in both zebrafish and mouse macrophages following injury. Adoptive transfer of macrophages, from resected zebrafish hearts into cryo-injured hosts and splenic monocyte-derived macrophages from adult mouse donors into neonatal hearts, 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, as further evidence of a direct macrophage contribution to collagen deposition and scar formation. These findings contrast with the current model of scarring, whereby collagen is laid down exclusively by myofibroblasts, and implicate macrophages as critical regulators of heart repair.
2019-12-18 | GSE126772 | GEO
Project description:Fibroblasts are activated to repair the heart following injury. Fibroblast activation in the mammalian heart leads to a permanent fibrotic scar that impairs cardiac function. In other organisms, such as zebrafish, cardiac injury is followed by transient fibrosis and scar-free regeneration. The mechanisms that drive scarring versus scar-free regeneration are not well understood. Here, we show that the homeobox-containing transcription factor Prrx1b is required for scar-free regeneration of the zebrafish heart as the loss of Prrx1b results in excessive fibrosis and impaired cardiomyocyte proliferation. Through lineage tracing and single-cell RNA sequencing we find that Prrx1b is activated in epicardial-derived cells where it restricts TGFβ ligand expression and collagen production. Furthermore, through combined in vitro experiments in human fetal epicardial-derived cells and in vivo rescue experiments in zebrafish, we conclude that Prrx1 stimulates Nrg1 expression and promotes cardiomyocyte proliferation. Collectively, these results indicate that Prrx1 is a key transcription factor that balances fibrosis and regeneration in the injured zebrafish heart.
2021-09-16 | GSE153170 | 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:Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair
| PRJNA523576 | ENA
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:After heart injury, adult zebrafish can perfectly regenerate its heart without any scar tissue left. We performed 100bp*2, paired-end, strand-specific, polyA-positive RNA-seq on hearts from 2 group of adult zebrafish, in which one was sham group and the other 7 days after heart tip amputation (7dpa). We found pathways involving hydrogen peroxidate related functions significantly up-regulated in 7dpa group, indicating its role in heart regeneration. RNA-seq: hearts from sham or 7dpa adult zebrafish
2014-12-24 | E-GEOD-50203 | biostudies-arrayexpress
Project description: Not available
| S-EPMC8138450 | biostudies-literature
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.
2015-11-05 | GSE74494 | GEO