Mendez Mario J, Hoffman Matthew J, Cherry Elizabeth M, Lemmon Christopher A, Weinberg Seth H
Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio; Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia.
School of Mathematical Sciences, Rochester Institute of Technology, Rochester, New York.
Biophys J. 2020 Apr 7;118(7):1749-1768. doi: 10.1016/j.bpj.2020.02.011. Epub 2020 Feb 15.
Epithelial-mesenchymal transition (EMT) is a fundamental biological process that plays a central role in embryonic development, tissue regeneration, and cancer metastasis. Transforming growth factor-β (TGFβ) is a potent inducer of this cellular transition, which is composed of transitions from an epithelial state to intermediate or partial EMT state(s) to a mesenchymal state. Using computational models to predict cell state transitions in a specific experiment is inherently difficult for reasons including model parameter uncertainty and error associated with experimental observations. In this study, we demonstrate that a data-assimilation approach using an ensemble Kalman filter, which combines limited noisy observations with predictions from a computational model of TGFβ-induced EMT, can reconstruct the cell state and predict the timing of state transitions. We used our approach in proof-of-concept "synthetic" in silico experiments, in which experimental observations were produced from a known computational model with the addition of noise. We mimic parameter uncertainty in in vitro experiments by incorporating model error that shifts the TGFβ doses associated with the state transitions and reproduces experimentally observed variability in cell state by either shifting a single parameter or generating "populations" of model parameters. We performed synthetic experiments for a wide range of TGFβ doses, investigating different cell steady-state conditions, and conducted parameter studies varying properties of the data-assimilation approach including the time interval between observations and incorporating multiplicative inflation, a technique to compensate for underestimation of the model uncertainty and mitigate the influence of model error. We find that cell state can be successfully reconstructed and the future cell state predicted in synthetic experiments, even in the setting of model error, when experimental observations are performed at a sufficiently short time interval and incorporate multiplicative inflation. Our study demonstrates the feasibility and utility of a data-assimilation approach to forecasting the fate of cells undergoing EMT.
上皮-间质转化(EMT)是一个基本的生物学过程,在胚胎发育、组织再生和癌症转移中起着核心作用。转化生长因子-β(TGFβ)是这种细胞转化的有效诱导剂,它由上皮状态向中间或部分EMT状态再到间质状态的转变组成。由于包括模型参数不确定性和与实验观测相关的误差等原因,使用计算模型预测特定实验中的细胞状态转变本质上是困难的。在本研究中,我们证明了一种使用集合卡尔曼滤波器的数据同化方法,该方法将有限的噪声观测与TGFβ诱导的EMT计算模型的预测相结合,可以重建细胞状态并预测状态转变的时间。我们在概念验证的“合成”计算机模拟实验中使用了我们的方法,在该实验中,实验观测是由一个已知的计算模型加上噪声产生的。我们通过纳入模型误差来模拟体外实验中的参数不确定性,该误差会改变与状态转变相关的TGFβ剂量,并通过改变单个参数或生成模型参数“群体”来再现实验观测到的细胞状态变异性。我们对广泛的TGFβ剂量进行了合成实验,研究了不同的细胞稳态条件,并进行了参数研究,改变了数据同化方法的属性,包括观测之间的时间间隔以及纳入乘法膨胀,乘法膨胀是一种补偿模型不确定性低估并减轻模型误差影响的技术。我们发现,即使在存在模型误差的情况下,当以足够短的时间间隔进行实验观测并纳入乘法膨胀时,细胞状态可以在合成实验中成功重建并预测未来的细胞状态。我们的研究证明了数据同化方法预测经历EMT的细胞命运的可行性和实用性。