Seebach Jochen, Taha Abdallah Abu, Lenk Janine, Lindemann Nico, Jiang Xiaoyi, Brinkmann Klaus, Bogdan Sven, Schnittler Hans-Joachim
Institute of Anatomy and Vascular Biology, Westfälische Wilhelms-Universität Münster, Vesaliusweg 2-4, 48149, Münster, Germany.
Faculty of Medicine Carl Gustav Carus, Fetscherstrasse 74, 01307, Dresden, Germany.
Histochem Cell Biol. 2015 Dec;144(6):517-32. doi: 10.1007/s00418-015-1357-8. Epub 2015 Aug 15.
Endothelial junctions are dynamic structures organized by multi-protein complexes that control monolayer integrity, homeostasis, inflammation, cell migration and angiogenesis. Newly developed methods for both the genetic manipulation of endothelium and microscopy permit time-lapse recordings of fluorescent proteins over long periods of time. Quantitative data analyses require automated methods. We developed a software package, the CellBorderTracker, allowing quantitative analysis of fluorescent-tagged cell junction protein dynamics in time-lapse sequences. The CellBorderTracker consists of the CellBorderExtractor that segments cells and identifies cell boundaries and mapping tools for data extraction. The tool is illustrated by analyzing fluorescent-tagged VE-cadherin the backbone of adherence junctions in endothelium. VE-cadherin displays high dynamics that is forced by junction-associated intermittent lamellipodia (JAIL) that are actin driven and WASP/ARP2/3 complex controlled. The manual segmentation and the automatic one agree to 90 %, a value that indicates high reliability. Based on segmentations, different maps were generated allowing more detailed data extraction. This includes the quantification of protein distribution pattern, the generation of regions of interest, junction displacements, cell shape changes, migration velocities and the visualization of junction dynamics over many hours. Furthermore, we demonstrate an advanced kymograph, the J-kymograph that steadily follows irregular cell junction dynamics in time-lapse sequences for individual junctions at the subcellular level. By using the CellBorderTracker, we demonstrate that VE-cadherin dynamics is quickly arrested upon thrombin stimulation, a phenomenon that was largely due to transient inhibition of JAIL and display a very heterogeneous subcellular and divers VE-cadherin dynamics during intercellular gap formation and resealing.
内皮细胞连接是由多蛋白复合物组成的动态结构,这些复合物控制着单层细胞的完整性、内环境稳定、炎症反应、细胞迁移和血管生成。新开发的内皮细胞基因操作方法和显微镜技术能够长时间对荧光蛋白进行延时记录。定量数据分析需要自动化方法。我们开发了一个软件包——细胞边界追踪器(CellBorderTracker),用于对延时序列中荧光标记的细胞连接蛋白动力学进行定量分析。细胞边界追踪器由细胞边界提取器(CellBorderExtractor)和数据提取映射工具组成,细胞边界提取器可对细胞进行分割、识别细胞边界。通过分析内皮细胞中黏附连接的主要成分——荧光标记的血管内皮钙黏蛋白(VE-cadherin),展示了该工具的作用。VE-钙黏蛋白表现出高度的动态性,这是由肌动蛋白驱动且受WASP/ARP2/3复合物控制的连接相关间歇性片状伪足(JAIL)所导致的。手动分割和自动分割的结果一致性达到90%,这一数值表明可靠性很高。基于分割结果,生成了不同的映射图,以便进行更详细的数据提取。这包括蛋白质分布模式的量化、感兴趣区域的生成、连接位移、细胞形状变化、迁移速度以及数小时内连接动力学的可视化。此外,我们展示了一种先进的波形图——J波形图,它能在亚细胞水平上稳定跟踪延时序列中单个连接的不规则细胞连接动力学。通过使用细胞边界追踪器,我们证明了凝血酶刺激后VE-钙黏蛋白动力学迅速停止,这一现象主要是由于JAIL的瞬时抑制,并且在细胞间隙形成和重新封闭过程中,VE-钙黏蛋白表现出非常异质的亚细胞和多样的动力学。
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