Cell-ECM contact-guided intracellular polarization is mediated via lamin A/C dependent nucleus-cytoskeletal connection
Cell-ECM contact-guided intracellular polarization is mediated via lamin A/C dependent nucleus-cytoskeletal connection
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DOI：
10.1016/j.biomaterials.2020.120548
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发表时间：
2021-01-01
期刊：
影响因子：
14
通讯作者：
Kim, Dong-Hwee
中科院分区：
文献类型：
--
作者：
Lee, Geonhui;Han, Seong-Beom;Kim, Dong-Hwee
细胞极化在细胞动态事件中起着至关重要的作用，如细胞增殖、分化和定向迁移，以响应各种细胞外和细胞内信号。虽然众所周知，细胞极化需要高度协调的细胞内分子重组，但细胞内细胞器在多种刺激下重新定位的潜在机制尚不清楚。在这里，我们发现基于细胞核和微管组织中心的相对位置的细胞前后极化是由包括细胞粘附到细胞外基质和核与细胞骨架连接在内的机械相互作用精确控制的。通过调节位于极化细胞形状模仿微图案的纤维连接蛋白涂覆的粘附点的大小和分布，我们监测了细胞极性的变化。我们发现单个粘附点的定位比细胞形状本身更能诱导细胞内极化。此外，通过破坏核层蛋白A/C，细胞极化程度显著降低。我们进一步证实，几何线索引导的细胞内极化通过Cdc42的局部激活决定了细胞的定向迁移。这些发现为细胞核-细胞骨架连接在单细胞极化中的作用提供了新的见解，在物理，分子和遗传线索的组合下，其中纤层蛋白a /C在通过细胞核-细胞骨架连接的ECM传感和信号转导中起关键的分子介质作用。
Cell polarization plays a crucial role in dynamic cellular events, such as cell proliferation, differentiation, and directional migration in response to diverse extracellular and intracellular signals. Although it is well known that cell polarization entails highly orchestrated intracellular molecular reorganization, the underlying mechanism of repositioning by intracellular organelles in the presence of multiple stimuli is still unclear. Here, we show that front-rear cell polarization based on the relative positions of nucleus and microtubule organizing center is precisely controlled by mechanical interactions including cellular adhesion to extracellular matrix and nucleuscytoskeletal connections. By modulating the size and distribution of fibronectin-coated adhesive spots located in the polarized cell shape mimicking micropatterns, we monitored the alterations in cell polarity. We found that the localization of individual adhesive spots is more dominant than the cell shape itself to induce intracellular polarization. Further, the degree of cell polarization was diminished significantly by disrupting nuclear lamin A/C. We further confirm that geometrical cue-guided intracellular polarization determines directional cell migration via local activation of Cdc42. These findings provide novel insights into the role of nucleus-cytoskeletal connections in single cell polarization under a combination of physical, molecular, and genetic cues, where lamin A/C acts as a critical molecular mediator in ECM sensing and signal transduction via nucleus-cytoskeletal connection.