Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts
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{"title"=>"Quantitative model of cell cycle arrest and cellular senescence in primary human fibroblasts", "type"=>"journal", "authors"=>[{"first_name"=>"Sascha", "last_name"=>"Schäuble", "scopus_author_id"=>"50263190500"}, {"first_name"=>"Karolin", "last_name"=>"Klement", "scopus_author_id"=>"22634749300"}, {"first_name"=>"Shiva", "last_name"=>"Marthandan", "scopus_author_id"=>"36523402000"}, {"first_name"=>"Sandra", "last_name"=>"Münch", "scopus_author_id"=>"23005627000"}, {"first_name"=>"Ines", "last_name"=>"Heiland", "scopus_author_id"=>"8941648600"}, {"first_name"=>"Stefan", "last_name"=>"Schuster", "scopus_author_id"=>"55323844600"}, {"first_name"=>"Peter", "last_name"=>"Hemmerich", "scopus_author_id"=>"7005515643"}, {"first_name"=>"Stephan", "last_name"=>"Diekmann", "scopus_author_id"=>"7004795132"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "isbn"=>"1932-6203", "pmid"=>"22879912", "scopus"=>"2-s2.0-84864654179", "doi"=>"10.1371/journal.pone.0042150", "sgr"=>"84864654179", "pui"=>"365398594"}, "id"=>"9ad31e31-fb92-37a0-b20d-6904c934dda7", "abstract"=>"Primary human fibroblasts in tissue culture undergo a limited number of cell divisions before entering a non-replicative \"senescent\" state. At early population doublings (PD), fibroblasts are proliferation-competent displaying exponential growth. During further cell passaging, an increasing number of cells become cell cycle arrested and finally senescent. This transition from proliferating to senescent cells is driven by a number of endogenous and exogenous stress factors. Here, we have developed a new quantitative model for the stepwise transition from proliferating human fibroblasts (P) via reversibly cell cycle arrested (C) to irreversibly arrested senescent cells (S). In this model, the transition from P to C and to S is driven by a stress function γ and a cellular stress response function F which describes the time-delayed cellular response to experimentally induced irradiation stress. The application of this model based on senescence marker quantification at the single-cell level allowed to discriminate between the cellular states P, C, and S and delivers the transition rates between the P, C and S states for different human fibroblast cell types. Model-derived quantification unexpectedly revealed significant differences in the stress response of different fibroblast cell lines. Evaluating marker specificity, we found that SA-β-Gal is a good quantitative marker for cellular senescence in WI-38 and BJ cells, however much less so in MRC-5 cells. Furthermore we found that WI-38 cells are more sensitive to stress than BJ and MRC-5 cells. Thus, the explicit separation of stress induction from the cellular stress response, and the differentiation between three cellular states P, C and S allows for the first time to quantitatively assess the response of primary human fibroblasts towards endogenous and exogenous stress during cellular ageing.", "link"=>"http://www.mendeley.com/research/quantitative-model-cell-cycle-arrest-cellular-senescence-primary-human-fibroblasts-1", "reader_count"=>51, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>15, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>3, "Student > Master"=>4, "Other"=>3, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>15, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>14, "Student > Postgraduate"=>3, "Student > Master"=>4, "Other"=>3, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>7, "Mathematics"=>2, "Agricultural and Biological Sciences"=>28, "Medicine and Dentistry"=>7, "Pharmacology, Toxicology and Pharmaceutical Science"=>3, "Physics and Astronomy"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>28}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>3}}, "reader_count_by_country"=>{"Canada"=>1, "Norway"=>1, "Brazil"=>1, "Germany"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/594762"], "description"=>"<p>a, proliferation; b, extension with second cell state species; c, complete final model (upper part: P-C-S transitions; lower part: stress induction and cell response function F).</p>", "links"=>[], "tags"=>["genetics and genomics", "cell biology", "developmental biology"], "article_id"=>265251, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042150.g002", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_scheme_/265251", "title"=>"Model scheme.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-07 01:27:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/594836"], "description"=>"<p>MRC-5. a, DNA damage marker γH2AX; b, cell cycle arrest marker p21; c, cycle arrest marker p16; d, senescence marker SA-β-Gal. The experimental error in such experiments is less than ±5%.</p>", "links"=>[], "tags"=>["mrc-5", "fibroblast", "cells", "cellular", "markers", "irradiation", "doses", "20"], "article_id"=>265317, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042150.g003", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relative_number_MRC_5_fibroblast_cells_positive_for_cellular_markers_after_irradiation_by_the_doses_0_0_5_and_20_Gy_/265317", "title"=>"Relative number MRC-5 fibroblast cells positive for cellular markers after irradiation by the doses 0, 0.5 and 20 Gy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-07 01:28:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/594962"], "description"=>"<p>Model fitting of different radiation doses and experimentally derived PDs. The data were fitted using the same parameter set for all radiation doses (differing only in the applied amount of irradiation time) applying the model described by Eq. 3a–d: a, MRC-5 fibroblast, different radiation doses 0, 0.5 and 20 Gy; b, WI-38 fibroblast, radiation doses 0, 2 and 15 Gy.</p>", "links"=>[], "tags"=>["curves"], "article_id"=>265450, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042150.g004", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PD_curves_of_human_fibroblasts_/265450", "title"=>"PD curves of human fibroblasts.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-07 01:30:50"}
  • {"files"=>["https://ndownloader.figshare.com/files/595059"], "description"=>"<p>a, Experimental growth data (circled) were fitted by model Eq. 3a–d using Eq. 4 as an expression for monotonically increasing stress γ; b, the fraction of proliferating cells P, cells showing a cell cycle arrest or a senescent phenotype (C+S) and solely the fraction of senescent cells S are shown together with the appearance of biomarkers. Biomarker values (p16, p21, SA-β-Gal and SAHF) were measured by immune-fluorescence as number of positive cells <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042150#pone.0042150-Klement1\" target=\"_blank\">[49]</a>.</p>", "links"=>[], "tags"=>["wi-38", "fibroblast"], "article_id"=>265549, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042150.g005", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulation_of_WI_38_fibroblast_data_/265549", "title"=>"Simulation of WI-38 fibroblast data.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-07 01:32:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/595182"], "description"=>"<p>a, experimental data (circled) were fitted by model Eq. 3a–d using Eq. 4 as an expression for monotonically increasing stress γ; b, the fraction of proliferating cells P, cells showing a cell cycle arrest or a senescent phenotype (C+S) and solely the fraction of senescent cells S are shown together with the appearance of biomarkers. Biomarker values (p16, p21, SA-β-Gal and SAHF) were measured by immune-fluorescence as number of positive cells <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042150#pone.0042150-Klement1\" target=\"_blank\">[49]</a>.</p>", "links"=>[], "tags"=>["bj", "fibroblast"], "article_id"=>265678, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042150.g006", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulation_of_BJ_fibroblast_data_/265678", "title"=>"Simulation of BJ fibroblast data.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-07 01:34:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/595476"], "description"=>"<p>f<sub>1</sub> values for model extension with cell cycle arrest species. Same experimental data as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042150#pone-0042150-t001\" target=\"_blank\">Table 1</a>. For all simulations parameter r  =  r<sub>max</sub> is set to 0.70 determined for HeLa cell growth rate and parameter f<sub>2</sub> to 1.</p>", "links"=>[], "tags"=>["parameter"], "article_id"=>265965, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042150.t002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Values_of_the_parameter_f_1_in_the_model_extension_/265965", "title"=>"Values of the parameter f<sub>1</sub> in the model extension.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-08-07 01:39:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/594656"], "description"=>"<p>See also <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042150#pone-0042150-t001\" target=\"_blank\">Table 1</a>.</p>", "links"=>[], "tags"=>["hela", "fibroblast", "cells", "circles", "dashed"], "article_id"=>265136, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042150.g001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fit_of_Eq_1_to_constant_growth_for_HeLa_own_data_green_squares_fit_blue_line_and_rat_fibroblast_cells_data_blue_circles_53_fit_red_dashed_line_/265136", "title"=>"Fit of Eq. 1 to constant growth for HeLa (own data: green squares, fit: blue line) and rat fibroblast cells (data: blue circles [<b>53</b>], fit: red dashed line).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-07 01:25:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/595443"], "description"=>"<p>Experimental data from the literature (rodent species <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042150#pone.0042150-Seluanov1\" target=\"_blank\">[53]</a>) and our own data (HeLa cells).</p>", "links"=>[], "tags"=>["parameter", "fitted"], "article_id"=>265934, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042150.t001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Constant_growth_model_parameter_r_fitted_to_experimental_data_/265934", "title"=>"Constant growth, model parameter r fitted to experimental data.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-08-07 01:38:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/595333"], "description"=>"<p>a, experimental data (circled) were fitted by model Eq. 3a–d using Eq. 4 as an expression for monotonically increasing stress γ; b, the fraction of proliferating cells P, cells showing a cell cycle arrest or a senescent phenotype (C+S) and solely the fraction of senescent cells S are shown together with the appearance of biomarkers. Biomarker values (p16, p21, SA-β-Gal and SAHF) were measured by immune-fluorescence as number of positive cells <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042150#pone.0042150-Klement1\" target=\"_blank\">[49]</a>.</p>", "links"=>[], "tags"=>["mrc-5", "fibroblast"], "article_id"=>265822, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042150.g007", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulation_of_MRC_5_fibroblast_data_/265822", "title"=>"Simulation of MRC-5 fibroblast data.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-07 01:37:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/311227", "https://ndownloader.figshare.com/files/311249", "https://ndownloader.figshare.com/files/311259"], "description"=>"<div><p>Primary human fibroblasts in tissue culture undergo a limited number of cell divisions before entering a non-replicative “senescent” state. At early population doublings (PD), fibroblasts are proliferation-competent displaying exponential growth. During further cell passaging, an increasing number of cells become cell cycle arrested and finally senescent. This transition from proliferating to senescent cells is driven by a number of endogenous and exogenous stress factors. Here, we have developed a new quantitative model for the stepwise transition from proliferating human fibroblasts (P) <em>via</em> reversibly cell cycle arrested (C) to irreversibly arrested senescent cells (S). In this model, the transition from P to C and to S is driven by a stress function γ and a cellular stress response function F which describes the time-delayed cellular response to experimentally induced irradiation stress. The application of this model based on senescence marker quantification at the single-cell level allowed to discriminate between the cellular states P, C, and S and delivers the transition rates between the P, C and S states for different human fibroblast cell types. Model-derived quantification unexpectedly revealed significant differences in the stress response of different fibroblast cell lines. Evaluating marker specificity, we found that SA-β-Gal is a good quantitative marker for cellular senescence in WI-38 and BJ cells, however much less so in MRC-5 cells. Furthermore we found that WI-38 cells are more sensitive to stress than BJ and MRC-5 cells. Thus, the explicit separation of stress induction from the cellular stress response, and the differentiation between three cellular states P, C and S allows for the first time to quantitatively assess the response of primary human fibroblasts towards endogenous and exogenous stress during cellular ageing.</p> </div>", "links"=>[], "tags"=>["quantitative", "cellular", "senescence", "fibroblasts"], "article_id"=>121397, "categories"=>["Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Sascha Schäuble", "Karolin Klement", "Shiva Marthandan", "Sandra Münch", "Ines Heiland", "Stefan Schuster", "Peter Hemmerich", "Stephan Diekmann"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0042150.s001", "https://dx.doi.org/10.1371/journal.pone.0042150.s002", "https://dx.doi.org/10.1371/journal.pone.0042150.s003"], "stats"=>{"downloads"=>5, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Quantitative_Model_of_Cell_Cycle_Arrest_and_Cellular_Senescence_in_Primary_Human_Fibroblasts/121397", "title"=>"Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-08-07 00:23:17"}

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Relative Metric

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