Cohesive and anisotropic vascular endothelial cell motility driving angiogenic morphogenesis
Cohesive and anisotropic vascular endothelial cell motility driving angiogenic morphogenesis
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DOI：
10.1038/s41598-019-45666-2
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发表时间：
2019-06-26
影响因子：
4.6
通讯作者：
Kurihara, Hiroki
中科院分区：
文献类型：
--
作者：
Takubo, Naoko;Yura, Fumitaka;Kurihara, Hiroki
血管内皮细胞在血管生成过程中表现出不均匀的集体迁移，称为“细胞混合”，其中细胞通过相互超越来改变它们的相对位置。然而，这种复杂的EC动力学如何导致高度有序的分支结构的形成仍然是未知的。为了揭示整合驱动血管生成形态发生的隐藏规律，我们使用小鼠主动脉外植体结合数学建模分析了体外血管生成发芽试验中的EC行为。从组织外植体周围的EC片延伸的芽的延时成像显示具有频繁U形转弯的定向内聚EC运动，其通常与尖端细胞超越相结合。孤立的分支剥夺基底细胞片的成像揭示了一个恒定的供应的迁移细胞的EC的分支前进的要求。相邻细胞之间通过彼此的各向异性吸引力可能是这些EC运动模式的基础，实验验证的数学模型证明。这些结果表明，各向异性的细胞间相互作用的凝聚运动的EC运动，这可能会驱动分支伸长取决于一个恒定的细胞供应的特点。目前的研究结果提供了新的见解，以细胞运动为基础的理解血管生成的形态发生。
Vascular endothelial cells (ECs) in angiogenesis exhibit inhomogeneous collective migration called "cell mixing", in which cells change their relative positions by overtaking each other. However, how such complex EC dynamics lead to the formation of highly ordered branching structures remains largely unknown. To uncover hidden laws of integration driving angiogenic morphogenesis, we analyzed EC behaviors in an in vitro angiogenic sprouting assay using mouse aortic explants in combination with mathematical modeling. Time-lapse imaging of sprouts extended from EC sheets around tissue explants showed directional cohesive EC movements with frequent U-turns, which often coupled with tip cell overtaking. Imaging of isolated branches deprived of basal cell sheets revealed a requirement of a constant supply of immigrating cells for ECs to branch forward. Anisotropic attractive forces between neighboring cells passing each other were likely to underlie these EC motility patterns, as evidenced by an experimentally validated mathematical model. These results suggest that cohesive movements with anisotropic cell-to-cell interactions characterize the EC motility, which may drive branch elongation depending on a constant cell supply. The present findings provide novel insights into a cell motility-based understanding of angiogenic morphogenesis.