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Project description:Spatiotemporal dysregulation of plasma fibrinogen synthesis unveils hepatic initiating role in MS and EAE pathogenesis
| PRJNA1375693 | ENA
Project description:Background & Aims: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSECs-expressed POFUT1 in liver fibrosis. Methods: Endothelial-specific Pofut1 knockout mice were generated and subjected to experimental liver fibrosis by chronic carbon tetrachloride exposure or by common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA-seq, qPCR, and Western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSECs cultures. Liver single-cell RNA-seq data sets from cirrhotic patients and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. Results: POFUT1 loss promoted injury-induced LSECs capillarization and HSC activation, leading to aggravated liver fibrosis. RNA-seq analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of cirrhotic patients. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to treatment with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. Conclusions: Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen which function as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/NOTCH/HES1/STAT3/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases.
2024-12-18 | GSE256179 | GEO
Project description:Fibrinogen is highly susceptible to oxidation compared to other plasma proteins. Fibrinogen oxidation damages its structure and affects the protein function. Fibrinogen was isolated from citrated human plasma by the modified cold ethanol precipitation technique. Oxidation of fibrinogen by ozone: a solution of 2.0 mg of fibrinogen in 1 ml of 0.05 M Tris/0.15 M NaCl buffer (pH 7.4) was introduced into a quartz reactor filled with ozone–oxygen mixture. The full exhaustion of ozone in each experiment was confirmed by spectrophotometry by the absorption band at 254 nm. The amount of ozone was varied in the range of 50–100 μM per 1 μM of fibrinogen. Ozone-induced oxidative modifications of the fibrinogen Aα, Bβ, and γ polypeptide chains upon addition of various amounts of the oxidizer have been studied by mass-spectrometry.
2019-04-04 | PXD012046 | Pride
Project description:The role of m6A RNA methylation in liver regeneration is unclear. This study aimed to determine the role of m6A methylation in liver regeneration after a 70% hepatectomy (HEPA) using liver specific Mettl 14 KO male mice. Analysis was conducted on post-operative days 1, 3, or 7 (HEPA1, 3, or 7) in control (FLOX) mice. In Flox mice, CyclinD1 protein expression was highest on postoperative day 3 (HEPA3) consistent with a dynamic increase in hepatocyte replication. The abundance of Mettl14 protein presented a similar pattern on HEPA3. Then, we performed hepatectomy in Mettl14 KOs (M14KO) and Flox controls and observed significantly higher post-surgical mortality in mutants. In Flox mice, CyclinD1 protein levels and Ki67 were markedly increased on HEPA3 compared to SHAM, while being downregulated in M14KO. Characterizing the m6A epitranscriptomic changes in Flox mice after hepatectomy and contrasting them to hepatectomy in M14KO in HEPA3 revealed enrichment for gene ontology terms associated with endoplasmic reticulum, inflammation, and apoptosis. Differentially methylated genes in M14KO compared to Flox on HEPA3 were also enriched for PPAR and AMPK signaling. Finally, we identified hypomethylated transcripts involved in fibrinogen synthesis, such as Fga, Fgb, and Fgg, by comparing differentially m6A-decorated genes in M14KO versus Flox on HEPA3. Knockdown of fibrinogen leads to suppression of proliferation via activation of p21 protein in AML12 cells. Together, m6A RNA methylation decorates genes involved in fibrinogen synthesis pointing to an important role in liver regeneration consistent with recent work demonstrating the significance of fibrinogen in liver regeneration.
2025-12-17 | GSE281071 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE18023: Mice with FIA develop anti-native and anti-in vitro citrullinated fibrinogen antibodies GSE18024: FIA plasma induces arthritis in naïve mice GSE18025: Fibrinogen-reactive T cells transfer disease to naïve mice Refer to individual Series
2010-05-05 | E-GEOD-18073 | biostudies-arrayexpress
Project description:Determination of the mechanism by which fibrinogen, a central blood coagulation protein drives immunological responses targeted to the CNS. Results identify the factors involved in the regulation and provide mechanistic basis. We subjected fibrinogen-injected corpus callosum to microarray to determine the genes involved in innate and adaptive immune responses by fibrinogen deposited in the CNS after blood-brain barrier disruption. Corpus callosum tissues were isolated from mice received stereotactic injection of fibrinogen or ACSF at 12 hr. Tissues were subjected for RNA extraction and hybridization on Affymatrix microarrays. Two ACSF and two fibrinogen samples were generated.
2015-09-16 | E-GEOD-71082 | biostudies-arrayexpress
Project description:Determination of the mechanism by which fibrinogen, a central blood coagulation protein drives immunological responses targeted to the CNS. Results identify the factors involved in the regulation and provide mechanistic basis. We subjected fibrinogen-injected corpus callosum to microarray to determine the genes involved in innate and adaptive immune responses by fibrinogen deposited in the CNS after blood-brain barrier disruption.
2015-09-16 | GSE71082 | GEO
Project description:characterization of fibrinogen expression in the kidney, excretion in the urine following kidney damage and evaluating the therapeutic potential of fibrinogen in acute kidney injury.
2011-10-01 | GSE27274 | GEO
Project description:Genetic opticospinal EAE (OSE) and MOG-induced EAE (MOG-EAE) are two experimental autoimmune encephalomyelitis (EAE) mouse models of human multiple sclerosis. For the OSE model, double-transgenic 2D2 (TCRMOG) x IgHMOG mice were used. For MOG-EAE, wildtype C57BL/6 mice were immunized with a MOG peptide consisting of the amino acids 35-55, administered in complete Freund’s adjuvant containing 5mg / ml Mycobacterium tuberculosi. The severity of EAE was rated on the scale 0: healthy animal; 1: animal with a flaccid tail; [...]; 4: animal with both hind legs paralyzed. The case groups in the experiment were: OSE1: OSE with disease score 1; OSE4: OSE with disease score 4; MOG4: MOG-EAE injected with both MOG and adjuvant, with disease score 4. The control groups in the experiment were: OSE0: OSE with disease score 0; CFA: C57BL/6 mice injected only with adjuvant (no MOG); WT: Wildtype C57BL/6 mice. The aim of the experiment was to assess gene expression differences 1) between OSE4 and OSE0, 2) between OSE1 and OSE0, and 3) between MOG4 and CFA. For control, WT was compared to OSE0 and CFA. Subsequently, differentially expressed transcripts were compared, first, between the OSE4 vs. OSE0 and the MOG4 vs. CFA contrasts (different EAE models) and, second, between the OSE4 vs. OSE0 and the OSE1 vs. OSE0 contrasts (different EAE severity).
2020-08-21 | E-MTAB-9132 | biostudies-arrayexpress
Project description:Perivacular fibroblasts (PVFs) in the perivascular space delaminate from blood vessels, expand, express and deposit an excess of collagen I (Col I) and become an integral component of the fibrotic scar after central nervous system (CNS) disease. Here, we show that blood-derived fibrinogen deposition in the perivascular space initially induces PVF activation after photothrombosis, a mouse model of ischemic stroke. Pharmacological fibrinogen depletion reduces PVF activation and their delamination from blood vessels to build up the fibrotic scar. Fibrinogen induces beta1 integrin signaling in PVF to induce Col I expression and secretion. Single-cell RNA sequencing (scRNA-Seq) and genetic approches revealed a contribution of fibrinogen-induced perivascular macrophages to PVF activation. Finally, fibrinogen depletion abrogates PVF-astrocyte signaling and astrocyte lesion border formation, promoting neuronal survival and plasticity. Therefore, we propose that fibrinogen is a critical trigger for PVF activation and fibrotic scar formation, inhibiting neuronal regeneration after stroke.
2025-12-04 | GSE291902 | GEO