Mutual interactions between telomere heterogeneity and cell culture growth dynamics shape stochasticity of cell aging
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Mathematical modeling and computational simulations are often used to explain the stochastic nature of cell aging. The models published thus far are based on the molecular mechanisms of telomere biology and how they dictate the dynamics of cell culture proliferation. However, the influence of cell growth conditions on telomere dynamics has been widely overlooked. These conditions include interactions with surrounding cells through contact inhibition, gradual accumulation of non-dividing cells, culture propagation and other cell culture maintenance factors. In order to follow the intrinsic growth dynamics of normal human fibroblasts we employed the fluorescent dye DiI and FACS analysis which can distinguish cells that undergo different numbers of divisions within culture. We observed rapid generation of cell subpopulations undergoing from 0 to 9 divisions within growing cultures at each passage analyzed. These large differences in number of divisions among individual cells guarantee a strong impact on generation of telomere length heterogeneity in normal cell cultures and suggest that culture conditions should be included in future modeling of cell senescence.
KeywordsTelomere Senescence Cell culture Cell proliferation DiI SA-β-galactosidase
We thank Mary Sopta for critically reading and editing the manuscript, Ela Kosor and Alenka Gagro for their participation in FACS analysis. We also thank Milena Ivanković, Marina Ferenac Kiš, Maja Matulić and Andrea Ćukušić Kalajžić for valuable discussions and practical assistance during the course of the experiments. This work was supported by Zaklada Adris.
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Conflict of interest
The authors declare that they have no conflict of interest.