Maintenance of Mechanical Tension for Normal Tissue Function Requires Intercellular Cooperation

维持正常组织功能的机械张力需要细胞间的合作

• 批准号: 1362922
• 负责人: Dimitrije Stamenovic
• 金额: $ 38.71万
• 依托单位: Trustees of Boston University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1362922&HistoricalAwards=false
• 关键词: Maintenance; Mechanical; Tension; Normal; Tissue

Mechanical stresses influence biological form and function. For normal functions, tissues must maintain stress at a preferred level a process known as tensional homeostasis. Various factors including injuries, diet, aging and genetic risk factors may disrupt tensional homeostasis, and loss of homeostasis promotes the progression of diseases including atherosclerosis, formation of aneurysm balloons, acute lung injury, and cancer. Although it is widely believed that tensional homeostasis traverses a wide range of length scales and that even single cells in isolation are capable of maintaining tensional homeostasis, preliminary data indicate that isolated cells are not capable of maintaining tensional homeostasis and that intercellular cooperation is required. This award will investigate how intercellular cooperation contributes to tensional homeostasis and to determine the underlying biophysical and biochemical mechanisms. The project will focus on homeostasis in vascular endothelial cells since vascular diseases are linked to a loss of tensional homeostasis. Results from this study will have a transformative impact on our understanding of the functional link between loss of tensional homeostasis and progression of diseases such as atherosclerosis and aneurysm. Furthermore, results of our study may provide insight into diseases such as cancer where the loss of tensional homeostasis is a hallmark of disease progression. The work will involve both undergraduate and graduate students and will be integrated into coursework.The dominant paradigm in vascular biology is that tensional homeostasis exists across multiple length (and time) scales through the feedback control of intracellular mechanics and signaling in response to the externally imposed stresses. However, preliminary data from this study revealed that isolated cells could not maintain tensional homeostasis, whereas confluent multicellular clusters could, suggesting that cell-cell interactions might be necessary for homeostasis. This leads to a working hypothesis that direct cell-cell interactions are required for maintaining tensional homeostasis in the endothelium. This is accomplished either via mechanical interdependence between adjacent cells, or via molecular crosstalk between adherens junctions and focal adhesions. To test this hypothesis, traction forces in cellular clusters and in individual cells will be measured using a micropattern traction microscopy system that was developed by the PIs. This technique utilizes multiple, distinct adhesion ligands and is compatible with substrate strain application mimicking the stretch conditions in vivo, application of shear flow mimicking vascular wall shear stress, tunable substrate rigidity, and high resolution microscopy to measure cellular traction forces with less than 1 nN accuracy.

机械应力影响生物形态和功能。 对于正常的功能，组织必须保持在一个优选的水平应力的过程称为张力稳态。 包括损伤、饮食、衰老和遗传风险因素在内的各种因素可能会破坏张力稳态，稳态的丧失会促进疾病的进展，包括动脉粥样硬化、动脉瘤球囊形成、急性肺损伤和癌症。 虽然人们普遍认为，张力稳态跨越了广泛的长度尺度，即使是孤立的单个细胞也能够维持张力稳态，但初步数据表明，孤立的细胞不能维持张力稳态，需要细胞间的合作。 该奖项将研究细胞间的合作如何有助于张力稳态，并确定潜在的生物物理和生化机制。 该项目将重点关注血管内皮细胞的动态平衡，因为血管疾病与张力动态平衡的丧失有关。 这项研究的结果将对我们理解张力稳态丧失与动脉粥样硬化和动脉瘤等疾病进展之间的功能联系产生变革性影响。 此外，我们的研究结果可能会提供深入了解疾病，如癌症，其中张力稳态的丧失是疾病进展的标志。这项工作将涉及本科生和研究生，并将被纳入coursework.The主导范式在血管生物学是张力稳态存在跨越多个长度（和时间）尺度，通过反馈控制细胞内的力学和信号，以响应外部施加的压力。 然而，这项研究的初步数据显示，孤立的细胞不能维持张力稳态，而汇合的多细胞簇可以，这表明细胞间的相互作用可能是必要的稳态。 这导致了一个工作假设，即直接的细胞-细胞相互作用是维持内皮张力稳态所必需的。 这是通过相邻细胞之间的机械相互依赖，或通过粘附连接和粘着斑之间的分子串扰来实现的。 为了验证这一假设，将使用PI开发的微图案牵引显微镜系统测量细胞簇和单个细胞中的牵引力。 该技术利用多种不同的粘附配体，并与模拟体内拉伸条件的基底应变应用、模拟血管壁剪切应力的剪切流应用、可调基底刚度和高分辨率显微镜兼容，以小于1 nN的精度测量细胞牵引力。

项目成果

Effect of correlation between traction forces on tensional homeostasis in clusters of endothelial cells and fibroblasts

牵引力对内皮细胞和成纤维细胞簇张力稳态的影响

• DOI: 10.1016/j.jbiomech.2019.109588
• 发表时间: 2020
• 期刊: Journal of biomechanics
• 影响因子: 2.4
• 作者: Barbone, PE;Smith, ML;Stamenovic, D
• 通讯作者: Stamenovic, D