A DNA-structured mathematical model of cell-cycle progression in cyclic hypoxia
A DNA-structured mathematical model of cell-cycle progression in cyclic hypoxia
复制标题
DOI：
10.1016/j.jtbi.2022.111104
复制
发表时间：
2022-05-16
影响因子：
2
通讯作者：
Byrne, Helen M.
中科院分区：
文献类型：
--
作者：
Celora, Giulia L.;Bader, Samuel B.;Byrne, Helen M.
新的实验数据表明，细胞周期性地暴露在低氧水平(即循环缺氧)中如何影响它们在细胞周期中的进展。在肿瘤中检测到周期性缺氧，并与预后不良和治疗失败有关。虽然波动的氧气环境可以在体外复制，但可以测试的氧循环范围是有限的。相比之下，数学模型可以用来预测对大范围循环动力学的响应。因此，在本文中，我们开发了一个细胞周期的机制模型，该模型可以与体外实验相结合，以更好地理解循环缺氧和细胞周期失调之间的联系。我们模型的一个显著特点是包含了DNA合成受损和由于周期性暴露于严重低氧水平而导致的细胞周期停滞。我们的模型将细胞群体分解成五个隔室，一个依赖于时间的延迟解释了S期持续时间的变异性，由于DNA合成速率的降低，严重缺氧时细胞的持续时间会增加。我们根据实验数据校准了我们的模型，并表明它概括了观察到的细胞周期动力学。我们使用校准的模型来研究细胞对尚未在实验中测试的氧循环的反应。当复氧期足够长时，我们的模型预测循环缺氧只是减缓细胞的增殖，因为细胞花费更多的时间在S阶段。相反，短时间的复氧周期被预测会导致增殖抑制，细胞被阻止在细胞周期的G2期。虽然短时间尺度(大约一天)的模型预测是相当准确的(即，可信区间很小)，但随着时间的延长，预测变得更加不确定。因此，我们使用我们的模型为实验设计提供信息，以改进模型参数估计并验证模型预测。(C)2022爱思唯尔有限公司版权所有。
New experimental data have shown how the periodic exposure of cells to low oxygen levels (i.e., cyclic hypoxia) impacts their progress through the cell-cycle. Cyclic hypoxia has been detected in tumours and linked to poor prognosis and treatment failure. While fluctuating oxygen environments can be reproduced in vitro, the range of oxygen cycles that can be tested is limited. By contrast, mathematical models can be used to predict the response to a wide range of cyclic dynamics. Accordingly, in this paper we develop a mechanistic model of the cell-cycle that can be combined with in vitro experiments to better understand the link between cyclic hypoxia and cell-cycle dysregulation. A distinguishing feature of our model is the inclusion of impaired DNA synthesis and cell-cycle arrest due to periodic exposure to severely low oxygen levels. Our model decomposes the cell population into five compartments and a time-dependent delay accounts for the variability in the duration of the S phase which increases in severe hypoxia due to reduced rates of DNA synthesis. We calibrate our model against experimental data and show that it recapitulates the observed cell-cycle dynamics. We use the calibrated model to investigate the response of cells to oxygen cycles not yet tested experimentally. When the re-oxygenation phase is sufficiently long, our model predicts that cyclic hypoxia simply slows cell proliferation since cells spend more time in the S phase. On the contrary, cycles with short periods of re-oxygenation are predicted to lead to inhibition of proliferation, with cells arresting from the cell-cycle in the G2 phase. While model predictions on short time scales (about a day) are fairly accurate (i.e, confidence intervals are small), the predictions become more uncertain over longer periods. Hence, we use our model to inform experimental design that can lead to improved model parameter estimates and validate model predictions.(c) 2022 Elsevier Ltd. All rights reserved.