quantitative model of cell cycle arrest and cellular senescence in primary human fibroblasts量化模型的细胞周期阻滞和细胞衰老主要人类成纤维细胞.pdfVIP

Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts ¨ 1,2 3¤a 3 ¨ 3¤b 2 Sascha Schauble , Karolin Klement , Shiva Marthandan , Sandra Munch , Ines Heiland , 2 3 3 Stefan Schuster , Peter Hemmerich , Stephan Diekmann * 1 Research Group Theoretical Systems Biology, Friedrich-Schiller-University, Jena, Germany, 2 Department of Bioinformatics, Friedrich-Schiller-University, Jena, Germany, 3 FLI, Beutenbergstr. 11, Jena, Germany 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 c 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 transiti