Contact-inhibited chemotaxis in de novo and sprouting blood-vessel growth.
Contact-inhibited chemotaxis in de novo and sprouting blood-vessel growth.
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DOI：
10.1371/journal.pcbi.1000163
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发表时间：
2008-09-19
影响因子：
4.3
通讯作者：
Glazier JA
中科院分区：
文献类型：
--
作者：
Merks RM;Perryn ED;Shirinifard A;Glazier JA
当分散的内皮细胞（完全形成的血管内壁的细胞）组织成血管网络（血管生成）时，或者通过现有血管的发芽或分裂（血管生成）时，血管就会形成。尽管它们在生物学上密切相关，但目前还没有模型用单一的生物物理机制解释这两种现象。大多数计算模型描述了血管水平的发芽，忽略了细胞行为如何驱动发芽过程中的分支分裂。我们提出了一种基于细胞的 Glazier-Graner-Hogeweg 模型（也称为细胞 Potts 模型），根据内皮细胞的合理行为，对血管索形成管腔之前的初始模式进行模拟。内皮细胞分泌化学引诱剂，吸引其他内皮细胞。与经典的凯勒-席格尔模型一样，趋化性本身会导致细胞聚集成孤立的簇。然而，在模拟中包括实验观察到的 VE-钙粘蛋白介导的趋化性接触抑制，会导致随机分布的细胞组织成网络和细胞聚集体发芽，从而再现从头和发芽血管生长的各个方面。我们讨论了导致我们结果的两个分支不稳定性。细胞簇表面的细胞试图迁移到细胞簇的中心，从而产生屈曲不稳定性。在消除表面法向力的模型变体中，耗散机制驱动发芽，分泌的化学物质既充当化学引诱剂又充当伪足延伸的抑制剂。如果力通过细胞外基质传递而不是化学信号传导介导细胞间相互作用，这两种机制也适用。造成我们结果的分支不稳定性是由趋化性的接触抑制引起的，既是通用的发育机制，也是异常模式不稳定性的有趣例子。如果我们需要在病理条件下（包括糖尿病、伤口愈合和肿瘤生长）增强或抑制血管生长，更好地了解内皮细胞（血管内壁的细胞）组织成血管的机制至关重要。在胚胎发育过程中，内皮细胞最初通过血管生长自组织成实心索网络。血管网络通过现有血管的分裂和发芽而扩张。通过计算机模拟，我们捕获了一小部分生物学上合理的细胞行为，这些行为可以重现内皮细胞的初始自组织、现有血管的萌芽以及随后对所得网络的立即重塑。在该模型中，内皮细胞既分泌可扩散的化学引诱剂，又通过伸展和缩回小伪足来向上移动这些化学物质的梯度。就其本身而言，这种行为会导致模拟细胞积累并聚集成大的圆形簇。我们提出，一旦膜接触到另一个内皮细胞的膜（接触抑制），内皮细胞就停止沿着细胞膜的给定部分延伸伪足。在我们的模拟中添加这种接触抑制可以使血管索在各种条件下形成芽。
Blood vessels form either when dispersed endothelial cells (the cells lining the inner walls of fully formed blood vessels) organize into a vessel network (vasculogenesis), or by sprouting or splitting of existing blood vessels (angiogenesis). Although they are closely related biologically, no current model explains both phenomena with a single biophysical mechanism. Most computational models describe sprouting at the level of the blood vessel, ignoring how cell behavior drives branch splitting during sprouting. We present a cell-based, Glazier–Graner–Hogeweg model (also called Cellular Potts Model) simulation of the initial patterning before the vascular cords form lumens, based on plausible behaviors of endothelial cells. The endothelial cells secrete a chemoattractant, which attracts other endothelial cells. As in the classic Keller–Segel model, chemotaxis by itself causes cells to aggregate into isolated clusters. However, including experimentally observed VE-cadherin–mediated contact inhibition of chemotaxis in the simulation causes randomly distributed cells to organize into networks and cell aggregates to sprout, reproducing aspects of both de novo and sprouting blood-vessel growth. We discuss two branching instabilities responsible for our results. Cells at the surfaces of cell clusters attempting to migrate to the centers of the clusters produce a buckling instability. In a model variant that eliminates the surface–normal force, a dissipative mechanism drives sprouting, with the secreted chemical acting both as a chemoattractant and as an inhibitor of pseudopod extension. Both mechanisms would also apply if force transmission through the extracellular matrix rather than chemical signaling mediated cell–cell interactions. The branching instabilities responsible for our results, which result from contact inhibition of chemotaxis, are both generic developmental mechanisms and interesting examples of unusual patterning instabilities. A better understanding of the mechanisms by which endothelial cells (the cells lining the inner walls of blood vessels) organize into blood vessels is crucial if we need to enhance or suppress blood vessel growth under pathological conditions, including diabetes, wound healing, and tumor growth. During embryonic development, endothelial cells initially self-organize into a network of solid cords via blood vessel growth. The vascular network expands by splitting of existing blood vessels and by sprouting. Using computer simulations, we have captured a small set of biologically plausible cell behaviors that can reproduce the initial self-organization of endothelial cells, the sprouting of existing vessels, and the immediately subsequent remodeling of the resulting networks. In this model, endothelial cells both secrete diffusible chemoattractants and move up gradients of those chemicals by extending and retracting small pseudopods. By itself, this behavior causes simulated cells to accumulate to aggregate into large, round clusters. We propose that endothelial cells stop extending pseudopods along a given section of cell membrane as soon as the membrane touches the membrane of another endothelial cell (contact inhibition). Adding such contact-inhibition to our simulations allows vascular cords to form sprouts under a wide range of conditions.
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影响因子：
2.7
作者：
Merks, RMH;Brodsky, SV;Glazier, JA
通讯作者：
Glazier, JA
影响因子：
8.6
作者：
GRANER, F;GLAZIER, JA
通讯作者：
GLAZIER, JA
影响因子：
1.7
作者：
Merks, RMH;Glazier, JA
通讯作者：
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影响因子：
1.3
作者：
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通讯作者：
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影响因子：
1.9
作者：
Levine, HA;Sleeman, BD;Nilsen-Hamilton, M
通讯作者：
Nilsen-Hamilton, M