Cell-Cell Adhesion Mechanics and Mechanotransduction at the Single Cell Level

单细胞水平的细胞-细胞粘附力学和力转导

• 批准号: 1826135
• 负责人: Ruiguo Yang
• 金额: $ 43.96万
• 依托单位: University of Nebraska-Lincoln
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1826135&HistoricalAwards=false
• 关键词: Cell; Adhesion; Mechanics; Mechanotransduction; Single

For cells to remain attached to their neighbors, there are cell-cell 'adhesion complexes.' These complexes are parts of the cell surface made up of very large adhesive molecules that transfer forces between the cells and hold them together. Mechanical coupling at adhesion complexes is necessary for many of the healthy behaviors of cells. Changes in the structure of the adhesion complex or of how the molecules change shape during stretching can cause diseases of the heart, joints (arthritis), and is part of the cellular story in cancer. The cell-cell junctions also are part of the cell's ability to detect how large the forces are on the tissue (mechanotransduction). One type of these junctions between cells, the 'desmosome', connects to the fiber network inside the cell to transmit forces and is not understood very well since most previous adhesion complex research has been done on the 'adherens' junction, which has different molecules and is associated with different diseases. This research project will reduce the huge knowledge gap about desmosomes with respect to their potential roles in mechanotransduction and disease control. The research will further the goals of the United States in developing the basic knowledge needed to understand and eventually treat medical conditions that are caused by failure of the desmosome to properly function. The research study will be integrated with existing University of Nebraska educational programs to offer undergraduate students experiences in mechanics, robotics, and cell biology. The PIs will also translate the research methodologies into a new course, "Cell Mechanics", in order to bring bioengineering-intensive knowledge into the current curriculum.Data from the PI's group have demonstrated the role of the desmosome-intermediate filament linkage in regulating cell mechanics, a role that has long been regarded to belong solely to the adherens junction. The research will determine the role that desmosomes play in cell-cell adhesion mechanics and in mechanotransduction. To achieve this goal, a novel device will be developed to provide in situ stimulation and interrogation of cell-cell junctions through defined mechanical tension. The platform will be able to stretch the mutual junction of a single pair of cells and simultaneously perform mechanical measurement, which will address the current challenge in interrogating cell-cell adhesion (i.e., difficulties in applying defined mechanical stimuli and conducting mechanical measurements at the same time). More importantly, integrated within an imaging system, the effect of mechanical stimuli on mechanotransduction pathways at the cell-cell junction can be monitored in real-time under applied load. With the platform, two fundamental scientific questions will be answered: (1) what is the contribution of desmosome and its link to intermediate filaments in maintaining cell-cell adhesion strength and (2) does the desmosome junction include mechanosensors that convert applied mechanical cues into biochemical signals to regulate cell behavior?This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

为了使细胞与它们的邻居保持附着，存在细胞-细胞粘附复合物。“这些复合物是细胞表面的一部分，由非常大的粘附分子组成，它们在细胞之间传递力并将它们保持在一起。 粘附复合物处的机械偶联对于细胞的许多健康行为是必要的。 粘附复合物结构的变化或分子在拉伸过程中如何改变形状的变化可能导致心脏、关节（关节炎）疾病，并且是癌症细胞故事的一部分。细胞-细胞连接也是细胞检测组织上的力有多大的能力的一部分（机械传导）。 细胞之间的这些连接的一种类型，即“桥粒”，连接到细胞内的纤维网络以传递力，并且还没有很好地理解，因为大多数以前的粘附复合物研究都是在“粘附”连接上进行的，其具有不同的分子并且与不同的疾病相关。 该研究项目将缩小关于桥粒在机械转导和疾病控制中的潜在作用的巨大知识差距。 这项研究将进一步促进美国的目标，即开发理解并最终治疗由桥粒无法正常发挥功能引起的疾病所需的基础知识。这项研究将与内布拉斯加大学现有的教育计划相结合，为本科生提供力学，机器人和细胞生物学方面的经验。PI还将把研究方法转化为一门新的课程“细胞力学”，以便将生物工程密集型知识纳入现有课程。PI小组的数据表明，桥粒-中间丝连接在调节细胞力学中的作用，长期以来一直被认为是只属于粘附连接的作用。这项研究将确定桥粒在细胞-细胞粘附力学和机械转导中的作用。为了实现这一目标，将开发一种新的装置，通过限定的机械张力提供原位刺激和询问细胞-细胞连接。该平台将能够拉伸单对细胞的相互连接并同时进行机械测量，这将解决当前在询问细胞-细胞粘附（即，难以同时施加限定的机械刺激和进行机械测量）。更重要的是，集成在成像系统中，可以在施加的负载下实时监测机械刺激对细胞-细胞连接处的机械转导途径的影响。有了这个平台，两个基本的科学问题将得到回答：（1）桥粒及其与中间丝在维持细胞-细胞粘附强度方面的贡献是什么？（2）桥粒连接是否包括将应用的机械信号转换为生化信号以调节细胞行为的机械传感器？该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估的支持。

项目成果

A multi-material platform for imaging of single cell-cell junctions under tensile load fabricated with two-photon polymerization

• DOI: 10.1007/s10544-022-00633-z
• 发表时间: 2022-10
• 期刊: Biomedical Microdevices
• 影响因子: 2.8
• 作者: J. Rosenbohm;Grayson Minnick;Bahareh Tajvidi Safa;A. M. Esfahani;Xiaowei Jin;Haiwei Zhai;N. Lavrik;Ruiguo Yang

Two‐Photon Polymerized Shape Memory Microfibers: A New Mechanical Characterization Method in Liquid

• DOI: 10.1002/adfm.202206739
• 发表时间: 2022-09
• 期刊: Advanced Functional Materials
• 影响因子: 19
• 作者: Grayson Minnick;Bahareh Tajvidi Safa;J. Rosenbohm;N. Lavrik;Justin R. Brooks;A. M. Esfahani;Alberto Samaniego;Fanben Meng;Benjamin Richter;Wei Gao;Ruiguo Yang

Nanosensors for single cell mechanical interrogation

• DOI: 10.1016/j.bios.2021.113086
• 发表时间: 2021-02-23
• 期刊: BIOSENSORS & BIOELECTRONICS
• 影响因子: 12.6
• 作者: Hang, Xinxin;He, Shiqi;Chang, Lingqian
• 通讯作者: Chang, Lingqian

Spatiotemporal Characterizations of Spontaneously Beating Cardiomyocytes with Adaptive Reference Digital Image Correlation

利用自适应参考数字图像相关性对自发搏动心肌细胞的时空表征

• DOI: 10.1038/s41598-019-54768-w
• 发表时间: 2019
• 期刊: Scientific Reports
• 影响因子: 4.6
• 作者: Shradhanjali, Akankshya;Riehl, Brandon D.;Duan, Bin;Yang, Ruiguo;Lim, Jung Yul
• 通讯作者: Lim, Jung Yul

Spatially Guided Construction of Multilayered Epidermal Models Recapturing Structural Hierarchy and Cell–Cell Junctions

• DOI: 10.1002/smsc.202200051
• 发表时间: 2022-09
• 期刊: Small Science
• 作者: Haiwei Zhai;Xiaowei Jin;Grayson Minnick;J. Rosenbohm;Mohammed Abdul Haleem Hafiz;Ruiguo Yang;Fanben Meng