Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA986064 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24981500_1.fastq.gz | Fastqsanger.gz | |||
| SRR24981500_2.fastq.gz | Fastqsanger.gz | |||
| SRR24981501_1.fastq.gz | Fastqsanger.gz | |||
| SRR24981501_2.fastq.gz | Fastqsanger.gz | |||
| SRR24981502_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:Scar tissue that forms in the heart after cardiac injury, comprises an abundant number of non-excitable fibroblasts in close proximity to excitable myocytes, that are embedded within the matrix of the scar. Electrical coupling of fibroblasts and myocytes is known to occur and in vitro simulation studies have demonstrated that changes in fibroblast membrane potential can lead to myocyte excitability and susceptibility to arrhythmogenesis. However, the physiologic significance of electrical coupling between myocytes and fibroblasts in scar tissue, in the regulation of cardiac excitability and arrhythmogenesis in vivo is hotly debated and has never been demonstrated. Here, we genetically engineer a mouse that expresses the optogenetic cationic channel ChR2 exclusively in cardiac fibroblasts and not in cardiac myocytes. We subject the animal to cardiac injury and demonstrate that optical stimulation of scar tissue elicits cardiac excitability and induces arrhythmias. Connexin 43 (Cx43) is a gap junctional protein that is the most abundant connexin isoform in the heart and thought to mediate electrical coupling of fibroblasts and myocytes. Using genetic loss of function approaches, we show that Cx43 is not necessary for fibroblast-myocyte electrical coupling in vivo. CRISPR/Cas 9 mediated sequential deletion of the other highly expressed connexins also did not affect electrical coupling of fibroblasts and myocytes. Using computational modeling approaches, we show that gap junctional and non-gap junctional coupling mechanisms synergize in a functionally redundant manner to excite myocytes coupled to fibroblasts. These observations demonstrate that cardiac fibroblasts in scar tissue directly regulate cardiac excitability in vivo and can induce arrhythmogenesis. Our findings throw insight into the importance of electrical coupling of fibroblasts and myocytes in the genesis of scar associated cardiac arrhythmias.
2023-09-28 | GSE235434 | GEO
Project description:After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated. We genetically engineered a mouse that expresses the optogenetic cationic channel ChR2 (H134R) exclusively in cardiac fibroblasts. After myocardial infarction, optical stimulation of scar tissue elicited organ-wide cardiac excitation and induced arrhythmias in these animals. Complementing computational modeling with experimental approaches, we showed that gap junctional and ephaptic coupling, in a synergistic yet functionally redundant manner, excited myocytes coupled to fibroblasts.
| S-EPMC10768850 | biostudies-literature
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:Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair
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Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
2024-11-17 | GSE240403 | GEO
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
2024-11-17 | GSE240400 | GEO
Project description:The mammalian heart possesses a poor ability to regenerate after acute ischemic cardiac injury and lost cardiac muscle is replaced by scar tissue. Multiple clinical studies demonstrate that the size of scar tissue following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors that regulate the size of scar after ischemic cardiac injury. In this report, we demonstrate that collagen V, a fibrillar collagen and a minor constituent of heart scars regulates the size of heart scars after ischemic cardiac injury. Depletion of collagen V in heart scars in two independent animal models led to a significant and paradoxical increase in post infarction scar tissue size with worsening of heart function. A systems genetics approach analyzing genes versus traits across 100 in-bred strains of mice independently demonstrated that collagen V is a critical driver of post injury heart function. We show that collagen V deficiency alters the ultra-structure and mechanical properties of scar tissue that make it more vulnerable to expansion. There is altered reciprocal feedback between matrix and cells that induce expression of specific mechanosensitive integrins which drive fibroblast activation and increased ECM gene expression. Scar size increases. Administration of cilengitide, an inhibitor of specific integrins, completely rescues the phenotype of increased post injury scarring, myofibroblast formation and cardiac dysfunction in collagen V deficient mice. These observations demonstrate that collagen V, a structural constituent of heart scar tissue regulates scar size in an integrin dependent manner.
2020-06-04 | GSE151695 | GEO
Project description:The mammalian heart possesses a poor ability to regenerate after acute ischemic cardiac injury and lost cardiac muscle is replaced by scar tissue. Multiple clinical studies demonstrate that the size of scar tissue following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors that regulate the size of scar after ischemic cardiac injury. In this report, we demonstrate that collagen V, a fibrillar collagen and a minor constituent of heart scars regulates the size of heart scars after ischemic cardiac injury. Depletion of collagen V in heart scars in two independent animal models led to a significant and paradoxical increase in post infarction scar tissue size with worsening of heart function. A systems genetics approach analyzing genes versus traits across 100 in-bred strains of mice independently demonstrated that collagen V is a critical driver of post injury heart function. We show that collagen V deficiency alters the ultra-structure and mechanical properties of scar tissue that make it more vulnerable to expansion. There is altered reciprocal feedback between matrix and cells that induce expression of specific mechanosensitive integrins which drive fibroblast activation and increased ECM gene expression. Scar size increases. Administration of cilengitide, an inhibitor of specific integrins, completely rescues the phenotype of increased post injury scarring, myofibroblast formation and cardiac dysfunction in collagen V deficient mice. These observations demonstrate that collagen V, a structural constituent of heart scar tissue regulates scar size in an integrin dependent manner.
2020-06-05 | GSE151834 | GEO
Project description:Myocardial fibrosis leads to cardiac dysfunction and arrhythmias in heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain poorly understood. Here, RNA sequencing identifies Forkhead Box1 (FoxO1) signaling as abnormal in HFpEF hearts. Genetic suppression of FoxO1 alters the intercellular communication between cardiomyocytes and fibroblasts, alleviates abnormal diastolic relaxation, and reduces arrhythmias. Targeted downregulation of FoxO1 in activated fibroblasts reduces cardiac fibrosis, blunts arrhythmogenesis and improves diastolic function in HFpEF. These results not only implicate FoxO1 in arrhythmogenesis and lusitropy but also demonstrate that pro-fibrotic cardiomyocyte-fibroblast communication can be corrected, constituting a novel therapeutic strategy for HFpEF.
2024-11-17 | GSE240401 | GEO