Computational modeling of angiogenesis : from matrix invasion to lumen formation

Computational modeling of angiogenesis : from matrix invasion to lumen formation
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血管生成的计算模型:从基质侵入到管腔形成

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发表时间:
2015
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影响因子:
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通讯作者:
Sonja E. M. Boas
Sonja E. M. Boas
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作者:
Sonja E. M. Boas

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在这篇论文中,计算模型被用来帮助解开血管生成的关键步骤,从现有的血管形成新的毛细血管的机制。血管生成的第一步是通过细胞外基质蛋白(例如纤维蛋白)的降解将新分支侵入周围组织。第一个模型描述了入侵的芽如何使用所谓的纤溶酶原系统,该系统溶解纤维蛋白基质。下一个模型研究内皮细胞如何在血管生成过程中动态转换位置。基于实验观察,几位作者认为动态细胞改组是在严格的遗传控制下进行的。然而,我们的模拟表明,洗牌可能会成为发芽的副作用。一旦芽形成,它需要中空以允许血液流动。这种中空或管腔形成的机制一直存在争议:空泡可能会在细胞中穿孔,或者细胞可能会相互排斥。在我们的模拟中,这两种假设都可以协同作用于管腔形成,这表明这两种假设可能一起工作。在最后一章中,我们介绍了一个工作流程,同时测试多个参数的值的变化对本文中使用的模型类型的结果的影响。
In this thesis computational modeling is used to help unravel the mechanisms of key steps in angiogenesis, the formation of new capillaries from existing blood vessels. The first step in angiogenesis is the invasion of new branches into the surrounding tissue by degradation of extracellular matrix proteins, e.g. fibrin. A first model describes how invading sprouts use the so called plasminogen system, which dissolves fibrin matrices. A next model asks how endothelial cells can dynamically switch position during angiogenesis. Based on experimental observations, several authors suggest that dynamic cell shuffling is under strict, genetic control. Our simulations show, however, that shuffling can emerge as a side effect of sprouting. Once a sprout is formed, it needs to hollow to allow blood flow. The mechanisms responsible for this hollowing, or lumen formation, are debated: vacuoles may punch a hole through the cell, or cells might repulse one another. In our simulations, both these hypotheses can work synergistically in lumen formation, suggesting that both hypotheses might work together. In a final chapter, we introduce a workflow to simultaneously test the impact of changes in the value of multiple parameters on the outcome of the type of models used in this thesis.
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