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Mathematical models incorporating a multi-stage cell cycle replicate normally-hidden inherent synchronization in cell proliferation.

ABSTRACT: We present a suite of experimental data showing that cell proliferation assays, prepared using standard methods thought to produce asynchronous cell populations, persistently exhibit inherent synchronization. Our experiments use fluorescent cell cycle indicators to reveal the normally hidden cell synchronization, by highlighting oscillatory subpopulations within the total cell population. These oscillatory subpopulations would never be observed without these cell cycle indicators. On the other hand, our experimental data show that the total cell population appears to grow exponentially, as in an asynchronous population. We reconcile these seemingly inconsistent observations by employing a multi-stage mathematical model of cell proliferation that can replicate the oscillatory subpopulations. Our study has important implications for understanding and improving experimental reproducibility. In particular, inherent synchronization may affect the experimental reproducibility of studies aiming to investigate cell cycle-dependent mechanisms, including changes in migration and drug response.

SUBMITTER: Vittadello ST

PROVIDER: S-EPMC6731503 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Mathematical models incorporating a multi-stage cell cycle replicate normally-hidden inherent synchronization in cell proliferation.

Vittadello Sean T ST McCue Scott W SW Gunasingh Gency G Haass Nikolas K NK Simpson Matthew J MJ

Journal of the Royal Society, Interface 20190821 157

We present a suite of experimental data showing that cell proliferation assays, prepared using standard methods thought to produce asynchronous cell populations, persistently exhibit inherent synchronization. Our experiments use fluorescent cell cycle indicators to reveal the normally hidden cell synchronization, by highlighting oscillatory subpopulations within the total cell population. These oscillatory subpopulations would never be observed without these cell cycle indicators. On the other h ...[more]

PMID: 31431185

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Project description:BackgroundThe biochemical oscillator that controls periodic events during the Xenopus embryonic cell cycle is centered on the activity of CDKs, and the cell cycle is driven by a protein circuit that is centered on the cyclin-dependent protein kinase CDK1 and the anaphase-promoting complex (APC). Many studies have been conducted to confirm that the interactions in the cell cycle can produce oscillations and predict behaviors such as synchronization, but much less is known about how the various elaborations and collective behavior of the basic oscillators can affect the robustness of the system. Therefore, in this study, we investigate and model a multi-cell system of the Xenopus embryonic cell cycle oscillators that are coupled through a common complex protein, and then analyze their synchronization ability under four different external stimuli, including a constant input signal, a square-wave periodic signal, a sinusoidal signal and a noise signal.ResultsThrough bifurcation analysis and numerical simulations, we obtain synchronization intervals of the sensitive parameters in the individual oscillator and the coupling parameters in the coupled oscillators. Then, we analyze the effects of these parameters on the synchronization period and amplitude, and find interesting phenomena, e.g., there are two synchronization intervals with activation coefficient in the Hill function of the activated CDK1 that activates the Plk1, and different synchronization intervals have distinct influences on the synchronization period and amplitude. To quantify the speediness and robustness of the synchronization, we use two quantities, the synchronization time and the robustness index, to evaluate the synchronization ability. More interestingly, we find that the coupled system has an optimal signal strength that maximizes the synchronization index under different external stimuli. Simulation results also show that the ability and robustness of the synchronization for the square-wave periodic signal of cyclin synthesis is strongest in comparison to the other three different signals.ConclusionsThese results suggest that the reaction process in which the activated cyclin-CDK1 activates the Plk1 has a very important influence on the synchronization ability of the coupled system, and the square-wave periodic signal of cyclin synthesis is more conducive to the synchronization and robustness of the coupled cell-cycle oscillators. Our study provides insight into the internal mechanisms of the cell cycle system and helps to generate hypotheses for further research.

Dataset Information

Mathematical models incorporating a multi-stage cell cycle replicate normally-hidden inherent synchronization in cell proliferation.

Publications

Mathematical models incorporating a multi-stage cell cycle replicate normally-hidden inherent synchronization in cell proliferation.

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