Endothelial tubes assemble from intracellular vacuoles in vivo
Endothelial tubes assemble from intracellular vacuoles in vivo
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DOI：
10.1038/nature04923
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发表时间：
2006-07-27
期刊：
影响因子：
64.8
通讯作者：
Weinstein, Brant M.
中科院分区：
文献类型：
--
作者：
Kamei, Makoto;Saunders, W. Brian;Weinstein, Brant M.
上皮管的形成对于许多不同组织和器官的正常发育至关重要，并通过各种不同的机制发生（1）。无缝的、适当图案化的内皮管的形态发生对于功能性脊椎动物循环系统的发育是必不可少的，但是体内血管管腔化的机制仍然不清楚。可以追溯到100多年前的证据表明，内皮空泡在管腔形成中具有重要功能（2）。超过25年前，在一些最早的体外内皮细胞培养实验中，Folkman和Haudenschild描述了“纵向空泡”，“似乎从一个细胞挤出并连接到下一个细胞”（3，4），后来的体外研究证实并扩展了观察结果，表明细胞内空泡是由整合素下游的整合素依赖性和cdc 42/Rac 1依赖性胞饮事件引起的。细胞外基质信号传导相互作用（5-10）。尽管有令人信服的数据支持的模型，通过形成和融合的空泡在体外组装的内皮管，在体内的确凿证据一直缺乏，主要是因为与成像的亚细胞内皮空泡在活体动物体内深处的动态相关的困难。在这里，我们使用转基因斑马鱼的高分辨率延时双光子成像来研究内皮管如何在体内组装，将我们的结果与体外三维胶原基质中人类内皮细胞管形成的延时成像进行比较。我们的研究结果为内皮细胞空泡的形成、细胞内和细胞间融合驱动血管腔形成的模型提供了有力的支持。
The formation of epithelial tubes is crucial for the proper development of many different tissues and organs, and occurs by means of a variety of different mechanisms(1). Morphogenesis of seamless, properly patterned endothelial tubes is essential for the development of a functional vertebrate circulatory system, but the mechanism of vascular lumenization in vivo remains unclear. Evidence dating back more than 100 years has hinted at an important function for endothelial vacuoles in lumen formation(2). More than 25 years ago, in some of the first endothelial cell culture experiments in vitro, Folkman and Haudenschild described "longitudinal vacuoles" that "appeared to be extruded and connected from one cell to the next"(3,4), observations confirmed and extended by later studies in vitro showing that intracellular vacuoles arise from integrin-dependent and cdc42/Rac1-dependent pinocytic events downstream of integrin - extracellular-matrix signalling interactions(5-10). Despite compelling data supporting a model for the assembly of endothelial tubes in vitro through the formation and fusion of vacuoles, conclusive evidence in vivo has been lacking, primarily because of difficulties associated with imaging the dynamics of subcellular endothelial vacuoles deep within living animals. Here we use high-resolution time-lapse two-photon imaging of transgenic zebrafish to examine how endothelial tubes assemble in vivo, comparing our results with time-lapse imaging of human endothelial-cell tube formation in three-dimensional collagen matrices in vitro. Our results provide strong support for a model in which the formation and intracellular and intercellular fusion of endothelial vacuoles drives vascular lumen formation.