Gene expression changes during senenscence in primary dermal human fibroblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE164446 | GEO | 2021/01/09
REPOSITORIES: GEO
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Project description:Telomere shortening in populations of human mammary epithelial cells (HMECs) that survive early replicative arrest (M0) by the inactivation of p16INK4A during cell culture on plastic dishes leads to a state of permanent replicative arrest termed senescence. While culture of HMECs on feeder layers abrogates M0 and p16INK4A inactivation, progressive telomere attrition in these cells also eventually results in permanent replicative arrest. Expression of telomerase prevents both senescence on plastic (S-P) and senescence on feeder layers (S-FL) in HMECs, as it does also in cultured primary human fibroblasts. We report here that the gene expression profiles of senescence in HMECs of the same lineage maintained under different culture conditions showed surprisingly little commonality. Moreover, neither of these senescence-associated profiles in HMECs resembles the profile for senescence in human fibroblasts. These results indicate that senescence-associated alterations in gene expression resulting from telomere attrition are affected by culture conditions as well as by cell origins, and argue that replicative senescence at the molecular level is a diverse rather than unique cellular process.
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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>
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Project description:Human primary fetal lung fibroblasts (HFL-1) undergoing replicative senescence
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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.
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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.
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