Targeting neural cell senescence reverses neuropsychiatric disorders
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE151307 | GEO | 2022/12/22
REPOSITORIES: GEO
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Project description:<p><strong>BACKGROUND:</strong> Periodontal ligament mesenchymal stem cells (PDLSCs) are a promising cell resource for cell-based regenerative medicine in dentistry. PDLSCs inevitably acquire a senescent phenotype after prolonged in vitro expansion, and the key regulators of cells during replicative senescence remain unclear.</p><p><strong>METHODS:</strong> We cultured periodontal ligament stem cells to passages 4, 10 and 20 (P4, P10, P20). The senescent phenotypes, proliferation and migration ability of PDLSCs (P4, P10, P20) were detected, and non-targeted metabonomic sequencing was performed. We treated PDLSCs with AICAR and detected the expression of FOXO1, FOXO3a, FOXO6 and AMPK phosphorylation (p-AMPK) levels of replicating senescent PDLSCs to explore the correlation between the metabolic changes and the AMPK pathway.</p><p><strong>RESULTS:</strong> Immunofluorescence staining of γ-H2AX, β-galactosidase staining, cell scratch test and qPCR were performed to confirm the occurrence of replicative senescence in PDLSCs during passaging. Three groups of cells at passage 4 (P4), passage 10 (P10) and passage 20 (P20) were collected for non-targeted metabolomics analysis. Metabonomic sequencing showed that the metabolism of replicative senescence in PDLSCs varied significantly. In particular, the content of fatty acid metabolites decreased with senescence, including capric acid, stearic acid, myristic acid and dodecanoic acid. KEGG pathway analysis showed that the AMPK signaling pathway was closely related to AMP levels. The AMP:ATP ratio increased in senescent PDLSCs; however, the levels of p-AMPK and the profile of FOXO1 and FOXO3a, which are downstream of the AMPK signaling pathway, decreased with senescence. We treated PDLSCs with AICAR, an activator of the AMPK pathway, and the phosphorylated AMPK level at P20 PDLSCs was partially restored. </p><p><strong>CONCLUSION:</strong> In summary, our study suggests that the metabolic process of PDLSCs is active in the early stage of senescence, prefers to consume fatty acids, and is attenuated in the later stages of senescence. AMP accumulates in replicative senescent PDLSCs; however, the sensitivity of AMPK phosphorylation sites is impaired, causing senescent PDLSCs to fail to respond to changes in energy metabolism. Our findings provide a new basis for the clinical application of periodontal ligament stem cells.</p>
2022-11-15 | MTBLS4568 | MetaboLights
Project description:Cellular senescence is classified into two types; replicative and premature senescence. Gene expression and epigenetic changes are different in types of senescence, replicative and premature senescence, and cell types. Normal human diploid fibroblast TIG-3 cells were often used in cellular senescence research, however, their epigenetic profiles were not fully understood. To elucidate how cellular senescence is epigenetically regulated in TIG-3 cells, we analyzed gene expression and DNA methylation profiles among three types of senescent cells, namely, replicative senescent, RAS-induced senescent (RIS) and non-permissive temperature-induced senescent SVts8 cells, using gene expression and methylation microarrays. The expression of genes involved in cell cycle and immune response were commonly either down- or up-regulated among three types of senescent cells, respectively. The sequential alteration of DNA methylation level was observed only in replicative senescent cells in a time-dependent manner, but not in premature senescent cells. The integrated analysis of gene expression and methylation in replicative senescent cells demonstrated that the expression of 759 genes involved in cell cycle and immune response was associated with methylation. Furthermore, hypomethylation occurred at non-CpG island regions (open sea) on the genes with increased expression as well as non-CpG promoter of the genes related to immune response. Several miRNAs regulated by DNA methylation were found to affect the expression of their target genes. Taken together, these results indicate that DNA methylation contributes to introduction and establishment of replicative senescence partly by regulating gene expression.
2017-02-12 | GSE81797 | GEO
Project description:Cellular senescence is classified into two types; replicative and premature senescence. Gene expression and epigenetic changes are different in types of senescence, replicative and premature senescence, and cell types. Normal human diploid fibroblast TIG-3 cells were often used in cellular senescence research, however, their epigenetic profiles were not fully understood. To elucidate how cellular senescence is epigenetically regulated in TIG-3 cells, we analyzed gene expression and DNA methylation profiles among three types of senescent cells, namely, replicative senescent, RAS-induced senescent (RIS) and non-permissive temperature-induced senescent SVts8 cells, using gene expression and methylation microarrays. The expression of genes involved in cell cycle and immune response were commonly either down- or up-regulated among three types of senescent cells, respectively. The sequential alteration of DNA methylation level was observed only in replicative senescent cells in a time-dependent manner, but not in premature senescent cells. The integrated analysis of gene expression and methylation in replicative senescent cells demonstrated that the expression of 759 genes involved in cell cycle and immune response was associated with methylation. Furthermore, hypomethylation occurred at non-CpG island regions (open sea) on the genes with increased expression as well as non-CpG promoter of the genes related to immune response. Several miRNAs regulated by DNA methylation were found to affect the expression of their target genes. Taken together, these results indicate that DNA methylation contributes to introduction and establishment of replicative senescence partly by regulating gene expression.
2017-02-12 | GSE81788 | GEO
Project description:Cellular senescence is classified into two types; replicative and premature senescence. Gene expression and epigenetic changes are different in types of senescence, replicative and premature senescence, and cell types. Normal human diploid fibroblast TIG-3 cells were often used in cellular senescence research, however, their epigenetic profiles were not fully understood. To elucidate how cellular senescence is epigenetically regulated in TIG-3 cells, we analyzed gene expression and DNA methylation profiles among three types of senescent cells, namely, replicative senescent, RAS-induced senescent (RIS) and non-permissive temperature-induced senescent SVts8 cells, using gene expression and methylation microarrays. The expression of genes involved in cell cycle and immune response were commonly either down- or up-regulated among three types of senescent cells, respectively. The sequential alteration of DNA methylation level was observed only in replicative senescent cells in a time-dependent manner, but not in premature senescent cells. The integrated analysis of gene expression and methylation in replicative senescent cells demonstrated that the expression of 759 genes involved in cell cycle and immune response was associated with methylation. Furthermore, hypomethylation occurred at non-CpG island regions (open sea) on the genes with increased expression as well as non-CpG promoter of the genes related to immune response. Several miRNAs regulated by DNA methylation were found to affect the expression of their target genes. Taken together, these results indicate that DNA methylation contributes to introduction and establishment of replicative senescence partly by regulating gene expression.
2017-02-12 | GSE81786 | GEO
Project description:Cellular senescence is classified into two groups; replicative and premature senescence. The gene expression and epigenetic changes differ between two groups of senescence, replicative and premature senescence, and cell types. Normal human diploid fibroblast TIG-3 cells have often been used in cellular senescence research, however, their epigenetic profiles are not fully understood. To elucidate how cellular senescence is epigenetically regulated in TIG-3 cells, we analyzed the gene expression and DNA methylation profiles of three types of senescent cells, namely, replicative senescent, ras-induced senescent (RIS), and non-permissive temperature-induced senescent SVts8 cells, using gene expression and methylation microarrays. The expression of genes involved in the cell cycle and immune response was commonly either down- or up-regulated in the three types of senescent cells, respectively. The sequential alteration of the DNA methylation level in a time-dependent manner was observed in replicatively senescent cells, but not in premature senescent cells. The integrated analysis of gene expression and methylation in replicatively senescent cells demonstrated that the expression of 759 genes involved in the cell cycle and immune response was associated with methylation. Furthermore, hypomethylation occurred in non-CpG island regions (open sea) of the genes exhibiting increased expression as well as non-CpG island promoters of the genes related to the immune response. Several miRNAs regulated through DNA methylation were found to affect the expression of their target genes. Taken together, these results indicate that DNA methylation contributes to the introduction and establishment of replicative senescence partly by regulating gene expression.
2017-02-12 | GSE90942 | GEO
Project description:Expression of the BRAFV600E oncoprotein is known to cause benign lesions, for example melanocytic nevi (moles). In spite of the oncogenic function of mutant BRAF, these lesions are arrested by a cell-autonomous mechanism called Oncogene-Induced Senescence (OIS). Infrequently, nevi can progress to malignant melanoma, through mechanisms that are incompletely understood. To gain more insight into this vital tumor suppression mechanism, we performed a mass spectrometry-based screening of the proteome and phosphoproteome in cycling and senescent cells as well as cells that have abrogated senescence. Proteome analysis of senescent cells revealed the upregulation of established senescence biomarkers, including specific cytokines, but also several proteins not previously associated with senescence, including extracellular matrix-interacting. Using both general and targeted phosphopeptide enrichment by Ti4+-IMAC and phosphotyrosine antibody enrichment, we identified over 15,000 phosphorylation sites. Among the regulated phosphorylation sites we encountered components of the interleukin, BRAF/MAPK and CDK-retinoblastoma (Rb) pathways and several other factors. The extensive proteome and phosphoproteome dataset of BRAFV600E-expressing senescent cells provides molecular clues as to how OIS is initiated, maintained or evaded, serving as a comprehensive proteomic basis for functional validation.
2015-01-13 | PXD001068 | Pride
Project description:Expression of the BRAFV600E oncoprotein is known to cause benign lesions, for example melanocytic nevi (moles). In spite of the oncogenic function of mutant BRAF, these lesions are arrested by a cell-autonomous mechanism called Oncogene-Induced Senescence (OIS). Infrequently, nevi can progress to malignant melanoma, through mechanisms that are incompletely understood. To gain more insight into this vital tumor suppression mechanism, we performed a mass spectrometry-based screening of the proteome and phosphoproteome in cycling and senescent cells as well as cells that have abrogated senescence. Proteome analysis of senescent cells revealed the upregulation of established senescence biomarkers, including specific cytokines, but also several proteins not previously associated with senescence, including extracellular matrix-interacting. Using both general and targeted phosphopeptide enrichment by Ti4+-IMAC and phosphotyrosine antibody enrichment, we identified over 15,000 phosphorylation sites. Among the regulated phosphorylation sites we encountered components of the interleukin, BRAF/MAPK and CDK-retinoblastoma (Rb) pathways and several other factors. The extensive proteome and phosphoproteome dataset of BRAFV600E-expressing senescent cells provides molecular clues as to how OIS is initiated, maintained or evaded, serving as a comprehensive proteomic basis for functional validation.
2015-01-12 | PXD000523 | Pride
Project description:Senescent cells release a variety of cytokines, proteases and growth factors collectively defined as the Senescent Secretory Associated Phenotype (SASP). Sustained SASP induces a pattern of chronic inflammation associated with aging and implicated in multiple age-related diseases. Here, we investigated the expression and function of the immunomodulatory cytokine BAFF (B-cell activating factor), a SASP factor, in multiple senescence models. First, we characterized BAFF production across different senescence models, including senescent human diploid fibroblasts (WI-38, IMR-90) and monocytic leukemia cells (THP-1), and tissues of mice induced to undergo senescence. We identified IRF1 (interferon response factor 1) as a transcription factor required for promoting BAFF mRNA transcription in senescence, and found that suppressing BAFF production decreased the senescent phenotype in both monocytes and fibroblasts. Importantly, the influence of BAFF on the senescence program was cell type-specific: in monocytes, BAFF promoted the early activation of NF-κB and general SASP secretion, while in fibroblasts, BAFF contributed to the production and function of TP53 (p53). Overall, BAFF silencing affected shared senescence-associated phenotypes including IL6 secretion, SA-beta-Gal staining, and γ-H2AX accumulation. We propose that BAFF is a novel biomarker of senescence and a potential target for senotherapy.
2023-04-07 | GSE213993 | GEO
Project description:In arthritis, synovial fibroblast (SF) senescence is linked to the activation of a pro-inflammatory phenotype contributing to chronic arthritis pathogenesis. Additionally, senescent cells accumulate in ageing tissues further promoting ageing and inflammation. These cells have dysregulated mitochondrial function and metabolism, limited tissue regeneration, produce reactive oxygen species (ROS) and secrete bioactive molecules, including pro-inflammatory cytokines, chemokines and matrix-remodelling enzymes known as SASP (senescence-associated secretory phenotype). In vitro, senescent cells can induce a senescent phenotype in surrounding bystander cells. Interestingly, extracellular vesicles (EVs) have critical roles in cellular senescence and ageing and are mediators in intercellular communication. We hypothesize that senescent cells in osteoarthritic SFs induce senescence and/or a proinflammatory phenotype in non-senescent osteoarthritic SFs, mediated through EV cargo.
2022-10-15 | PXD032757 | Pride
Project description:Senescence is a permanent cell cycle arrest that occurs in response to cellular stress. Because senescent cells promote age-related disease, there has been considerable interest in defining the proteomic alterations in senescent cells. Because senescence differs greatly depending on cell type and senescence inducer, continued progress in the characterization of senescent cells is needed. Here, we analyzed primary human mammary epithelial cells (HMECs), a model system for aging, using mass spectrometry-based proteomics. By integrating data from replicative senescence, immortalization by telomerase reactivation, and drug-induced senescence, we identified a robust proteomic signature of HMEC senescence consisting of 77 upregulated and 36 downregulated proteins. This approach identified known biomarkers, such as downregulation of the nuclear lamina protein lamin-B1 (LMNB1), and novel upregulated proteins including the β-galactoside-binding protein galectin-7 (LGALS7). Gene ontology enrichment analysis demonstrated that senescent HMECs upregulated lysosomal proteins and downregulated RNA metabolic processes. We additionally integrated our proteomic signature of senescence with transcriptomic data from senescent HMECs to demonstrate that our proteomic signature can discriminate proliferating and senescent HMECs even at the transcriptional level. Taken together, our results demonstrate the power of proteomics to identify cell type-specific signatures of senescence and advance the understanding of senescence in primary HMECs.
2021-09-28 | PXD027318 | Pride