Inverse modeling using multi-block PLS to determine the environmental conditions that provide optimal cellular function
Inverse modeling using multi-block PLS to determine the environmental conditions that provide optimal cellular function
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DOI：
10.1093/bioinformatics/btg433
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发表时间：
2004-03-01
期刊：
影响因子：
5.8
通讯作者：
Chan, C
中科院分区：
文献类型：
--
作者：
Hwang, DH;Stephanopoulos, G;Chan, C
动机：组织工程是一个重要领域，具有解决当前器官可用性短缺问题的潜力。为了成功开发组织工程器官，至关重要的是了解如何在最大限度发挥其生理作用的能力的条件下维持细胞，无论环境如何，无论细胞是体外系统的一部分，例如生物人工肝辅助装置还是可植入的组织工程装置。我们的目标是 (1) 深入了解细胞在面临环境变化时的行为方式，以及 (2) 确定实现所需细胞功能水平的最佳环境因素。结果：使用不同的环境因素来系统性地干扰与预处理和血浆补充相关的代谢行为。为了探测肝细胞的代谢状态，使用代谢流分析来获得代谢概况。我们应用多块偏最小二乘（MPLS）模型将环境因素和通量与细胞内脂质和尿素合成水平联系起来。 MPLS 模型确定了：(1) 最有影响力的环境因素以及 (2) 这些因素如何改变代谢途径。最后，我们反转 MPLS 模型，以确定获得最经济的解决方案所需的环境因素的浓度和类型，以实现实际情况下细胞功能的最佳水平。
Motivations: Tissue engineering constitutes an important field with its potential of addressing the current shortage in organ availability. To successfully develop tissue-engineered organs, it is crucial to understand how to maintain the cells under conditions that maximize their ability to perform their physiological roles, regardless of the environment, whether the cells are part of an extracorporeal system, such as the bioartificial liver assist device, or an implantable tissue-engineered device. Our goals are to (1) provide insight into how cells will behave when confronted with changes in its environment and (2) determine the optimal environmental factors to achieve a desired level of cellular function.Results: Diverse sets of environmental factors were used to systematically perturb the metabolic behavior associated with pre-conditioning and plasma supplementation. To probe metabolic state of hepatocytes, metabolic flux analysis was used to obtain the metabolic profile. We applied a multi-block partial least square (MPLS) model to relate environmental factors and fluxes to levels of intracellular lipids and urea synthesis. The MPLS model identified: (1) the most influential environmental factors and (2) how the metabolic pathways are altered by these factors. Finally, we inverted the MPLS model to determine the concentrations and types of environmental factors required to obtain the most economical solution for achieving optimal levels of cellular function for practical situations.