Transient ACE Inhibition Suppresses Future Fibrogenic Capacity and Heterogeneity of Cardiac Fibroblast Subpopulations
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PROVIDER: PRJNA655239 | ENA |
REPOSITORIES: ENA
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Project description:Transient angiotensin converting enzyme (ACE) inhibition in spontaneously hypertensive rats (SHR) protects against future injury-induced cardiac inflammation, fibrosis, and dysfunction. Here, we used single cell RNA sequencing (scRNA-Seq) to test the hypothesis that transient ACE inhibitor treatment would induce a persistent shift in hypertensive cardiac fibroblast subpopulations. Adult male SHRs (11 weeks old) were treated for 2 weeks with an ACE inhibitor, enalapril (30mg/kg/day, p.o.), or water (control) followed by a 2-week washout period (n=7/group). Cardiac fibroblasts were isolated from the left ventricle and subjected to scRNA-Seq. Nine clusters of fibroblasts (numbered 0-8) were identified with 98% of cells clustering into subsets 0-6. Transient treatment produced significant changes within and across clusters. Cluster 1 depicted the highly fibrogenic gene profile, with cluster 6 serving as a gateway to cluster 1. Transient ACE inhibition depleted the gateway and expanded cluster 0, which was the least fibrogenic profile. Moreover, within cluster 1 fibroblasts, ACE inhibition reduced expression of individual fibrosis genes (e.g. COL1A1, COL3A1, and FN1; all p<0.05). Clusters 2-5 reflected proliferative, moderately fibrogenic, translationally active, and lowly inflammatory subsets of fibroblasts, all of which exhibit attenuated fibrogenic gene expression after transient ACE inhibition. In conclusion, transient ACE inhibition shifts cardiac fibroblast subpopulations and degree of activation resulting in an overall reduced fibrogenic phenotype.
2020-10-01 | GSE155699 | GEO
Project description:Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular Dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered-tracing mice, we demonstrate that in dystrophic muscle, specialized cells of muscular, endothelial and hematopoietic origins gain plasticity towards a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity was also observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component. TGFb exposure induced gene expression was measured after 4 days of treatment compared to untreated cells. Three independent experiments were performed both for the treatment and for the control
2015-04-09 | E-GEOD-67687 | biostudies-arrayexpress
Project description:Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular Dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered-tracing mice, we demonstrate that in dystrophic muscle, specialized cells of muscular, endothelial and hematopoietic origins gain plasticity towards a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity was also observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component.
2015-04-09 | GSE67687 | GEO
Project description:Differential responses to stimuli can affect how cells succumb to disease. In yeast, DNA damage can create heterogeneous responses. To delineate how a response contributes to a cell's future behavior, we constructed a transcription-based memory circuit that detects DNA repair to isolate subpopulations with heritable damage responses. Strongly responsive cells show multigenerational effects, including growth defects and iron-associated gene expression. Less-responsive cells exhibit increased mutation frequencies but resume wild-type behavior. These two subpopulations remain distinct for multiple generations, indicating a transmissible memory of damage. Collectively, this work demonstrates the efficacy of using synthetic biology to define how environmental exposure contributes to distinct cell fates. Cells containing the HUG1 memory device (Burrill, 2011) were exposed to 0.3% EMS for 24 h and recovered for 36 h, at which point cells were sorted based on YFP expression, i.e. memory and non-memory cells. These two sorted populations were then grown for another 12 h, at which point transcriptional profiling was performed.
2012-03-02 | E-GEOD-36210 | biostudies-arrayexpress
Project description:Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nano-sized extracellular vesicles (EVs) and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated upregulation of EV-related pathways in the liver pericentral zone, which was abrogated by the glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs upregulated the expression of EV-related genes such as RAB31 by enhancing histone-3-lysine-9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
2024-05-16 | PXD050337 | Pride
Project description:Differential responses to stimuli can affect how cells succumb to disease. In yeast, DNA damage can create heterogeneous responses. To delineate how a response contributes to a cell's future behavior, we constructed a transcription-based memory circuit that detects DNA repair to isolate subpopulations with heritable damage responses. Strongly responsive cells show multigenerational effects, including growth defects and iron-associated gene expression. Less-responsive cells exhibit increased mutation frequencies but resume wild-type behavior. These two subpopulations remain distinct for multiple generations, indicating a transmissible memory of damage. Collectively, this work demonstrates the efficacy of using synthetic biology to define how environmental exposure contributes to distinct cell fates.
2012-03-02 | GSE36210 | GEO
Project description:Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs) and the release of fibrogenic nano-sized extracellular vesicles (EVs). Activated HSCs increase their glucose metabolism via glycolysis to satisfy high energy demands. Nevertheless, the mechanism of how glycolysis in HSCs coordinates fibrosis amplification in the fibrogenic zones in the liver is elusive and is the scope of this study. Single cell RNA sequencing (scRNAseq) and bulk RNAseq demonstrated that several glycolysis enzymes, including hexokinase 2 (HK2), were upregulated in activated HSCs. HSC-selective glycolysis-deficient mice (HK2ΔHSC) showed abrogated CCl4-mediated fibrosis as compared to littermate controls (HK2fl/fl). Spatial transcriptomics revealed an upregulation of several EV-related pathways in the fibrotic pericentral zone during liver fibrosis in control HK2fl/fl mice. However, glycolysis-deficient HK2ΔHSC mice showed downregulation of these EV-related pathways in the pericentral zone. Consistently, induction of glycolysis in HSCs in vitro, either by glucose or platelet-derived growth factor B (PDGF), upregulated the expression of several extracellular vesicle (EV)-related genes, including RAB31. Glycolysis in HSCs epigenetically enhanced RAB31 expression through histone-3 lysine-9 acetylation (H3K9ac) on the promoter region, leading to increased EV release. Functionally, glycolysis-dependent EVs were enriched with fibrogenic molecules and increased the expression of fibrotic markers in recipient HSCs. Finally, EVs derived from glycolysis-deficient HK2ΔHSC mice abrogated liver fibrosis amplification as compared to EVs derived from littermate control HK2fl/fl mice. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the pericentral fibrotic regions in the liver.
2024-03-20 | GSE259363 | GEO
Project description:A variety of epigenetic alterations impairs functions of cells and tissues during aging, but it is not known if epigenetic alterations are associated with aging muscle. Here, we examined the changes of a panel of histone marks and found H3K27ac (an active enhancer mark) is markedly increased during aging in human skeletal muscle tissues. Our integrated analysis showed that enhancer activation during muscle aging is associated with the up-regulation of extracelluar matrix (ECM) genes, which may result in stiffness of the niche environment of satellite cells (SCs). An age-related fibrogenic conversion of geriatric SCs was observed through differential gene expression analysis. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation reverted the ECM up-regulation and fibrogenic conversion of SCs, suggesting that ECM increase in aging muscle is indeed a result of enhancer activation. The study here not only uncovered a novel aspect of muscle aging that is associated with enhancer remodeling but also highlighted JQ1 as a potential treatment approach for restoring SC function in aging muscle.
2019-08-15 | GSE122867 | GEO
Project description:Three glioblastoma subpopulations were analyzed by quantitative proteomics, using dimethyl labeling approach. Deconvolution of mixture spectra using SuperQuant software was employed to increase the depth of quantification.
2018-03-08 | PXD005245 | Pride