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Cited by 39Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSkin Protection and Aging

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Conserved genes and pathways in primary human fibroblast strains undergoing replicative and radiation induced senescence

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Marthandan, Shiva, Menzel, Uwe, Priebe, Steffen, Groth, Marco, Guthke, Reinhard, Platzer, Matthias, Hemmerich, Peter, Kaether, Christoph, Diekmann, Stephan·2016·Biological Research
DOI 10.1186/s40659-016-0095-2PMC PMC4963952
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Abstract

BACKGROUND: Cellular senescence is induced either internally, for example by replication exhaustion and cell division, or externally, for example by irradiation. In both cases, cellular damages accumulate which, if not successfully repaired, can result in senescence induction. Recently, we determined the transcriptional changes combined with the transition into replicative senescence in primary human fibroblast strains. Here, by γ-irradiation we induced premature cellular senescence in the fibroblast cell strains (HFF and MRC-5) and determined the corresponding transcriptional changes by high-throughput RNA sequencing. RESULTS: Comparing the transcriptomes, we found a high degree of similarity in differential gene expression in replicative as well as in irradiation induced senescence for both cell strains suggesting, in each cell strain, a common cellular response to error accumulation. On the functional pathway level, "Cell cycle" was the only pathway commonly down-regulated in replicative and irradiation-induced senescence in both fibroblast strains, confirming the tight link between DNA repair and cell cycle regulation. However, "DNA repair" and "replication" pathways were down-regulated more strongly in fibroblasts undergoing replicative exhaustion. We also retrieved genes and pathways in each of the cell strains specific for irradiation induced senescence. CONCLUSION: We found the pathways associated with "DNA repair" and "replication" less stringently regulated in irradiation induced compared to replicative senescence. The strong regulation of these pathways in replicative senescence highlights the importance of replication errors for its induction.

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Figures

Fig. 1 Percentage of SA-β gal positive cells in MRC-5 fibroblasts ±Gy irradiation. Young MRC-5 strains (PD34) were subjected to different doses of Gamma irradiation (0, 2, 15, 20 Gy) and the percentage of SA-β Gal positive cells were determined at different time points after irradiation treatment. Between 80 and 100 cells were analyzed for each data point. The bars indicate the mean ±SD. Values statistically different from their controls (0 Gy irradiation) are indicated with an asterix (t-test): *p < 0.05, **p < 0.01, ***p < 0.001. n = 3 in all cases
Fig. 1 Percentage of SA-β gal positive cells in MRC-5 fibroblasts ±Gy irradiation. Young MRC-5 strains (PD34) were subjected to different doses of Gamma irradiation (0, 2, 15, 20 Gy) and the percentage of SA-β Gal positive cells were determined at different time points after irradiation treatment. Between 80 and 100 cells were analyzed for each data point. The bars indicate the mean ±SD. Values statistically different from their controls (0 Gy irradiation) are indicated with an asterix (t-test): *p < 0.05, **p < 0.01, ***p < 0.001. n = 3 in all casesCC BY · PubMed Central
Fig. 2 Percentage of SA-β Gal positive cells in HFF strains ± Gy irradiation. Young HFF strains (PD20) were subjected to no and 20 Gy of gamma irradiation (0, 20 Gy) and the percentage of SA-β gal positive cells were measured at different time points after irradiation treatment. Between 80 and 100 cells were analyzed for each data point. The bars indicate the mean ±S.D. Values statistically different from their controls (0 Gy irradiation) are indicated with an asterix (t-test): *p < 0.05, ***p < 0.001. n = 3 in all cases
Fig. 2 Percentage of SA-β Gal positive cells in HFF strains ± Gy irradiation. Young HFF strains (PD20) were subjected to no and 20 Gy of gamma irradiation (0, 20 Gy) and the percentage of SA-β gal positive cells were measured at different time points after irradiation treatment. Between 80 and 100 cells were analyzed for each data point. The bars indicate the mean ±S.D. Values statistically different from their controls (0 Gy irradiation) are indicated with an asterix (t-test): *p < 0.05, ***p < 0.001. n = 3 in all casesCC BY · PubMed Central
Fig. 3 Variance and sample clustering of normalized transcriptome expression values principal component analysis (PCA) of young MRC-5 (triangles) and HFF (spheres) fibroblast cells of low PDs (MRC-5: 32, HFF: 16) subjected to 0 (control, green) and 20 Gy (blue) irradiation. Triplicates (identical symbol and color) are clustered indicating small experimental errors
Fig. 3 Variance and sample clustering of normalized transcriptome expression values principal component analysis (PCA) of young MRC-5 (triangles) and HFF (spheres) fibroblast cells of low PDs (MRC-5: 32, HFF: 16) subjected to 0 (control, green) and 20 Gy (blue) irradiation. Triplicates (identical symbol and color) are clustered indicating small experimental errorsCC BY · PubMed Central
Fig. 4 Immunoblots reveal protein expression levels of markers having a role in induction of senescence. The levels of induction of these proteins in fibroblasts at different cell states are demonstrated (low PD, low PD + 20 Gy irradiation (after 120 h), replicative senescence). The up- or down-regulation was signified by the presence or absence of the bands. p21, p16, IGFBP7, IGFBP3, IGFBP5 were up-regulated to a similar extent in irradiation induced as well as in replicatively senescent cells. In contrast, Id3 was down-regulated in both cases, in replicative stronger than in irradiation induced senescence, and in HFF stronger than in MRC-5 strains
Fig. 4 Immunoblots reveal protein expression levels of markers having a role in induction of senescence. The levels of induction of these proteins in fibroblasts at different cell states are demonstrated (low PD, low PD + 20 Gy irradiation (after 120 h), replicative senescence). The up- or down-regulation was signified by the presence or absence of the bands. p21, p16, IGFBP7, IGFBP3, IGFBP5 were up-regulated to a similar extent in irradiation induced as well as in replicatively senescent cells. In contrast, Id3 was down-regulated in both cases, in replicative stronger than in irradiation induced senescence, and in HFF stronger than in MRC-5 strainsCC BY · PubMed Central
Fig. 5 Regulation of genes of Cell Cycle pathway during senescence induction in HFF strains. Genes of the “cell cycle” pathway which are significantly up- (green) and down- (red) regulated (log2 fold change >1) during irradiation induced senescence (120 h after 20 Gy irradiation) in HFF strains. Orange and blue colors signify genes which are commonly up- (orange) and down-regulated (blue) during both, irradiation induced and replicative senescence
Fig. 5 Regulation of genes of Cell Cycle pathway during senescence induction in HFF strains. Genes of the “cell cycle” pathway which are significantly up- (green) and down- (red) regulated (log2 fold change >1) during irradiation induced senescence (120 h after 20 Gy irradiation) in HFF strains. Orange and blue colors signify genes which are commonly up- (orange) and down-regulated (blue) during both, irradiation induced and replicative senescenceCC BY · PubMed Central
Fig. 6 Regulation of genes of cell cycle pathway during senescence induction in MRC-5 strains. Genes of the “cell cycle” pathway which are significantly up- (green) and down- (red) regulated (log2 fold change >1) during irradiation induced senescence (120 h after 20 Gy irradiation) in MRC-5 fibroblasts. Blue color signifies genes which are commonly down-regulated during both, irradiation induced and replicative senescence
Fig. 6 Regulation of genes of cell cycle pathway during senescence induction in MRC-5 strains. Genes of the “cell cycle” pathway which are significantly up- (green) and down- (red) regulated (log2 fold change >1) during irradiation induced senescence (120 h after 20 Gy irradiation) in MRC-5 fibroblasts. Blue color signifies genes which are commonly down-regulated during both, irradiation induced and replicative senescenceCC BY · PubMed Central

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Metadata

Authors
Marthandan, S., Menzel, U., Priebe, S., Groth, M., Guthke, R., Platzer, M., Hemmerich, P., Kaether, C., & Diekmann, S.
Affiliations
  • Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
  • Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE)
Corresponding author
Marthandan, Shiva
ORCID
Venue
Biological Research
Publisher
Springer Science and Business Media LLC
Published
2016-07-28
Volume
49
Issue
1
Pages
34-34
ISSN
  • 0716-9760 (ISSN-L)
  • 0717-6287
DOI
10.1186/s40659-016-0095-2
PMC
PMC4963952
OpenAlex
W2491783232
Cited by
39
References
210
Citations by year
2026: 1 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 2 · 2019: 6 · 2018: 5 · 2017: 2
FWCI
3.49
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Biological Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
  • Americanae (AECID Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion, cc-by)
Funders
Bundesministerium für Bildung und Forschung– BMBF (0315581)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Dermatology › Skin Protection and Aging
Keywords
cellular senescence, replicative senescence, radiation-induced senescence, gamma irradiation, primary human fibroblasts, DNA repair, DNA replication, cell cycle regulation, transcriptome, differential gene expression, DNA damage accumulation, MRC-5 cells
MeSH terms
Analysis of Variance, beta-Galactosidase, Cells, Cultured, DNA Damage, DNA Repair, DNA Replication, Fibroblasts, Gamma Rays, Humans, Lung, Male, Time Factors, Immunoblotting, Down-Regulation, Up-Regulation, Cellular Senescence, Sequence Analysis, RNA, Gene Expression Profiling, Aborted Fetus

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