Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, United Kingdom.
Instituto de Medicina Molecular-João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
PLoS Comput Biol. 2021 Feb 4;17(2):e1007715. doi: 10.1371/journal.pcbi.1007715. eCollection 2021 Feb.
During developmental angiogenesis, endothelial cells respond to shear stress by migrating and remodelling the initially hyperbranched plexus, removing certain vessels whilst maintaining others. In this study, we argue that the key regulator of vessel preservation is cell decision behaviour at bifurcations. At flow-convergent bifurcations where migration paths diverge, cells must finely tune migration along both possible paths if the bifurcation is to persist. Experiments have demonstrated that disrupting the cells' ability to sense shear or the junction forces transmitted between cells impacts the preservation of bifurcations during the remodelling process. However, how these migratory cues integrate during cell decision making remains poorly understood. Therefore, we present the first agent-based model of endothelial cell flow-mediated migration suitable for interrogating the mechanisms behind bifurcation stability. The model simulates flow in a bifurcated vessel network composed of agents representing endothelial cells arranged into a lumen which migrate against flow. Upon approaching a bifurcation where more than one migration path exists, agents refer to a stochastic bifurcation rule which models the decision cells make as a combination of flow-based and collective-based migratory cues. With this rule, cells favour branches with relatively larger shear stress or cell number. We found that cells must integrate both cues nearly equally to maximise bifurcation stability. In simulations with stable bifurcations, we found competitive oscillations between flow and collective cues, and simulations that lost the bifurcation were unable to maintain these oscillations. The competition between these two cues is haemodynamic in origin, and demonstrates that a natural defence against bifurcation loss during remodelling exists: as vessel lumens narrow due to cell efflux, resistance to flow and shear stress increases, attracting new cells to enter and rescue the vessel from regression. Our work provides theoretical insight into the role of junction force transmission has in stabilising vasculature during remodelling and as an emergent mechanism to avoid functional shunting.
在发育性血管生成过程中，内皮细胞通过迁移和重塑最初的分支状丛来响应剪切应力，去除某些血管，同时保持其他血管。在这项研究中，我们认为血管保留的关键调节因子是分叉处的细胞决策行为。在流动汇聚的分叉处，当迁移路径发散时，如果分叉要保持下去，细胞必须精细地调整沿两条可能路径的迁移。实验表明，破坏细胞感知剪切力或细胞之间传递的连接力的能力会影响分叉在重塑过程中的保留。然而，细胞决策过程中这些迁移线索如何整合仍然知之甚少。因此，我们提出了第一个适合研究分叉稳定性背后机制的基于代理的内皮细胞流动介导迁移模型。该模型模拟了由代表内皮细胞的代理组成的分支血管网络中的流动，这些代理排列在腔中并沿流动方向迁移。当接近存在多个迁移路径的分叉时，代理会参考随机分叉规则，该规则模拟了细胞作为基于流动和基于集体的迁移线索的组合做出的决策。根据该规则，细胞倾向于具有相对较大剪切应力或细胞数量的分支。我们发现，细胞必须几乎平等地整合这两个线索，以最大限度地提高分叉稳定性。在具有稳定分叉的模拟中，我们发现了流动和集体线索之间的竞争振荡，而失去分叉的模拟无法维持这些振荡。这两个线索之间的竞争是血流动力学起源的，表明在重塑过程中存在防止分叉丢失的自然防御机制：由于细胞流出导致血管腔变窄，流动和剪切应力的阻力增加，吸引新的细胞进入并从回归中拯救血管。我们的工作为连接力传递在重塑过程中稳定血管以及作为避免功能分流的新兴机制方面的作用提供了理论见解。
