Shokhirev Maxim N, Almaden Jonathan, Davis-Turak Jeremy, Birnbaum Harry A, Russell Theresa M, Vargas Jesse A D, Hoffmann Alexander
Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA San Diego Center for Systems Biology, UCSD, La Jolla, CA, USA Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.
Department of Chemistry and Biochemistry, Signaling Systems Laboratory, UCSD, La Jolla, CA, USA Biological Sciences Graduate Program, UCSD, La Jolla, CA, USA.
Mol Syst Biol. 2015 Feb 13;11(1):783. doi: 10.15252/msb.20145554.
Understanding the functions of multi-cellular organs in terms of the molecular networks within each cell is an important step in the quest to predict phenotype from genotype. B-lymphocyte population dynamics, which are predictive of immune response and vaccine effectiveness, are determined by individual cells undergoing division or death seemingly stochastically. Based on tracking single-cell time-lapse trajectories of hundreds of B cells, single-cell transcriptome, and immunofluorescence analyses, we constructed an agent-based multi-modular computational model to simulate lymphocyte population dynamics in terms of the molecular networks that control NF-κB signaling, the cell cycle, and apoptosis. Combining modeling and experimentation, we found that NF-κB cRel enforces the execution of a cellular decision between mutually exclusive fates by promoting survival in growing cells. But as cRel deficiency causes growing B cells to die at similar rates to non-growing cells, our analysis reveals that the phenomenological decision model of wild-type cells is rooted in a biased race of cell fates. We show that a multi-scale modeling approach allows for the prediction of dynamic organ-level physiology in terms of intra-cellular molecular networks.
从每个细胞内的分子网络角度理解多细胞器官的功能，是从基因型预测表型这一探索过程中的重要一步。B淋巴细胞群体动态可预测免疫反应和疫苗效果，它由单个细胞看似随机地进行分裂或死亡所决定。基于对数百个B细胞的单细胞延时轨迹追踪、单细胞转录组分析和免疫荧光分析，我们构建了一个基于主体的多模块计算模型，以根据控制NF-κB信号传导、细胞周期和细胞凋亡的分子网络来模拟淋巴细胞群体动态。通过结合建模与实验，我们发现NF-κB的cRel通过促进生长中的细胞存活来强制执行互斥命运之间的细胞决策。但由于cRel缺陷导致生长中的B细胞以与非生长细胞相似的速率死亡，我们的分析表明野生型细胞的现象学决策模型植根于细胞命运的偏向性竞争。我们表明，多尺度建模方法能够根据细胞内分子网络预测动态器官水平的生理学。
