计算生物学
计算机科学
系统生物学
基因调控网络
生物信息学
计算模型
人工智能
模拟生物系统
机器学习
作者
Diego Marescotti,Tommaso Serchi,Karsta Luettich,Yang Xiang,Elisa Moschini,Marja Talikka,Florian Martin,Karine Baumer,Remi Dulize,Dariusz Peric,David Bornand,Emmanuel Guedj,Alain Sewer,Sebastian Cambier,Servane Contal,Aline Chary,Arno C. Gutleb,Stefan Frentzel,Nikoloai V Ivanov,Manuel C. Peitsch,Julia Hoeng
出处
期刊:ALTEX-Alternatives to Animal Experimentation
日期:2019-01-01
卷期号:36 (3): 388-402
被引量:9
标识
DOI:10.14573/altex.1811221
摘要
To more accurately model inhalation toxicity in vitro, we developed a tetra-culture system that combines lung alveolar epithelial cells, endothelial cells, macrophages, and mast cells in a three-dimensional orientation. We characterized the influence of the added complexity using network perturbation analysis and gene expression data. This will allow us to gain insight into the steady-state profile of the assembled, complete three-dimensional model using all four cell types and of simpler models of one, two, or three cell types. Gene expression data were analyzed using cause-and-effect biological network models, together with a quantitative network-scoring algorithm, to determine the biological impact of co-culturing the various cell types. In the assembled tetra-culture, macrophages appeared to be the largest contributors to overall network perturbations, promoting high basal levels of oxidative stress and inflammation. This finding led to further optimization of the model using rested macrophages; the addition of rested macrophages decreased the basal inflammatory and cell stress status of the co-culture. Finally, we compared transcriptional profiles from publicly available datasets of conventional in vitro models representative of the airways and of healthy human lung tissues to assess similarities between our model and other in vitro models and the human lung. On the transcriptional level, we found an increasing correlation between airway models and normal human lung tissue, particularly as cell types became more physiologically relevant and the complexity of the system increased. This indicates that the combination of multiple lung-relevant cell types in vitro does indeed increase similarity to the physiological counterpart.
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