Cell-specific ablation of Hsp47 defines the collagen producing cells in the injured heart
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE129612 | GEO | 2019/08/22
REPOSITORIES: GEO
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Project description: Not available
| S-EPMC6693833 | biostudies-literature
Project description:Cell-specific ablation of Hsp47 defines the collagen producing cells in the injured heart
| PRJNA531932 | ENA
Project description:Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell-type in terms of their origins and functional effects in vivo. Methods: Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen inducible Cre for cellular lineage tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Results: Lineage tracing with 4 additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after myocardial infarction. Periostin-traced myofibroblasts also revert back to a less activated state upon injury resolution. Conclusions: Our results define the myofibroblast as a periostin-expressing cell-type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts. Fluidigm C1 whole genome transcriptome analysis of lineage mapped cardiac myofibroblasts
2016-06-14 | E-GEOD-83337 | biostudies-arrayexpress
Project description:Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell-type in terms of their origins and functional effects in vivo. Methods: Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen inducible Cre for cellular lineage tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Results: Lineage tracing with 4 additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin+ myofibroblasts reduces collagen production and scar formation after myocardial infarction. Periostin-traced myofibroblasts also revert back to a less activated state upon injury resolution. Conclusions: Our results define the myofibroblast as a periostin-expressing cell-type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21+ tissue-resident fibroblasts.
2016-06-14 | GSE83337 | GEO
Project description:Cardiomyopathy is characterized by the deposition of extracellular matrix by activated resident cardiac fibroblasts, called myofibroblasts. A current lack of therapeutic approaches to blunt the development of pathological fibrosis and ventricle chamber stiffening that ultimately leads to heart failure necessitates the investigation of the mechanisms that underlie myofibroblast activation. We previously observed that increased degradation of p53 occurs during the cardiac fibroblast expansion phase that acutely follows pressure overload. We created tissue-specific mouse models to delete p53 in quiescent resident cardiac fibroblasts and in activated myofibroblasts, then evaluated consequences to cardiac physiology, cellular biology, and fibrotic remodeling. We then performed RNA sequencing to further elucidate the effects of p53 deletion in cardiac fibroblasts on gene expression at the single cell level. We confirmed these results with a series of in vitro experiments in primary mouse cardiac fibroblasts. Results - Here, we demonstrate that p53 knockout in resident cardiac fibroblasts significantly accelerates proliferation and temporarily insulates the heart from fibrotic remodeling and functional decline in response to pressure overload, but ultimately results in a more deleterious phenotype than in wildtype animals. Conversely, p53 knockout in activated myofibroblasts does not result in a delay in functional loss, and is uniformly deleterious to the heart. Single-cell RNA sequencing revealed that p53 knockout is associated with the development of constitutively mitotic fibroblasts, and increased recruitment of fibroblasts into a main activation trajectory that involves four states: quiescent, early transitional, late transitional, and fully activated. A quiescent, functionally specialized vascular support fibroblast population that is ubiquitous in the wildtype animal is additionally recruited into activation in the p53 knockout condition, resulting in the eventual extreme functional decline seen in these animals. In vitro experimentation using viral deletion of p53 supports these findings - quiescent fibroblasts lacking p53 are resistant to activation, but activated myofibroblasts lacking p53 do not reverse their activation. This was found to be due to parallel hyperactivation of Cdkn2a/Rb1-mediated G1 cell cycle arrest in the p53 knockout condition, which was supported by in vivo studies. Conclusions - These data establish p53 as a major regulator of the myofibroblast activation response to pressure overload. Moreover, the single-cell studies establish an activation trajectory for resident cardiac fibroblasts, and elucidate the fundamental importance of clinical intervention prior to irreversible myofibroblast activation seen in chronic stages of pressure overload.
2023-06-23 | GSE165455 | GEO
Project description:Brain metastases (BrMs) are the leading cause of death in patients with solid cancers. BrMs exhibit a highly immunosuppressive milieu and poor response to immunotherapies; however, the underlying mechanism remains largely unclear. Here, we show that upregulation of HSP47 in tumor cells drives metastatic colonization and outgrowth in brain by creating an immunosuppressive microenvironment. HSP47-mediated collagen deposition in the metastatic niche promotes microglial polarization to M2 phenotype via the α2β1 integrin/NF-κB pathway, which upregulates the anti-inflammatory cytokines and represses CD8+ T cell anti-tumor responses. Depletion of microglia reverses HSP47-induced inactivation of CD8+ T cells and abolishes brain metastasis. Col003, an inhibitor disrupting HSP47-collagen association restores an anti-tumor immunity and enhances the efficacy of anti-PD-L1 immunotherapy in BrMs-bearing mice. Our study supports that HSP47 is a critical determinant of M2 microglial polarization and immunosuppression, and blocking the HSP47-collagen axis represents a promising therapeutic strategy against brain metastatic tumors.
2024-03-22 | GSE261941 | GEO
Project description:Cardiac fibroblasts (CFs) are the primary cells tasked with depositing and remodeling collagen and significantly associated with heart failure (HF). TEAD1 has been shown to be essential for heart development and homeostasis. However, endogenous fibroblast TEAD1 in cardiac remodeling remains incompletely understood. Transcriptomic analyses revealed consistently upregulated cardiac TEAD1 expression in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Further investigation revealed that CFs were the primary cell type expressing elevated TEAD1 levels in response to pressure overload. Conditional TEAD1 knockout was achieved by crossing TEAD1-floxed mice with CFs- and myofibroblasts-specific Cre mice. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency and treatment with TEAD1 inhibitor, VT103, ameliorated TAC-induced cardiac remodeling. Mechanistically, RNA-seq analysis identified Wnt4 as a novel TEAD1 target. TEAD1 has been shown to promote the fibroblast-to-myofibroblast transition through the Wnt signalling pathway, and genetic Wnt4 knockdown inhibited the pro-transformation phenotype in CFs with TEAD1 overexpression. Furthermore, co-immunoprecipitation combined with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated interaction between TEAD1 and BET protein BRD4, leading to the binding and activation of the Wnt4 promoter. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway.
2023-12-28 | GSE251976 | GEO
Project description:Activation of fibroblasts is a hallmark of fibrotic processes. Besides cytokines and growth factors, fibroblasts are regulated by the extracellular matrix environment through receptors such as integrins, which transduce biochemical and mechanical signals enabling cells to mount appropriate responses according to biological demands. The aim of this work was to investigate the in vivo role of collagen–fibroblast interactions for regulating fibroblast functions and fibrosis.
2023-11-08 | PXD046778 | Pride
Project description:Overall goal: To elucidate fibroblast-specific role of TGFβ-Smad2/3 signaling in fibroblast activation and their differentiation to myofibroblasts. Purpose of analysis: To generate transcriptional profile of Smad2/3 and TGFβreceptors1/2-deficient fibroblasts in the context of pathological cardiac fibrosis.
2017-10-25 | GSE101772 | GEO
Project description:To explore the mechanisms for SOCS3 in cardiomyocytes to regulate cardiac hypertrophic remodeling after pressure overload, we therefore performed proteomic analysis to identify novel protein targets or pathways in left ventricular samples from SOCS3 knockout (SOCS3cko) mice and their WT littermates.
2021-09-08 | PXD014946 | Pride