Effects of Stretch and Intercellular Force Transmission on Tensional Homeostasis in Multicellular Clusters

拉伸和细胞间力传递对多细胞簇张力稳态的影响

• 批准号: 1910401
• 负责人: Dimitrije Stamenovic
• 金额: $ 52.9万
• 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: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1910401&HistoricalAwards=false
• 关键词: Effects; Stretch; Intercellular; Force; Transmission

The ability of living cells to maintain their internal mechanical stress in response to external disturbances is essential for normal physiological functions of cells and tissues and for a protection against various diseases. This is known as tensional homeostasis. Breakdown of tensional homeostasis is the hallmark of most advanced solid cancers (carcinomas), as well as of stiffening of the arteries (atherosclerosis) and clot formation (thrombosis). While physical interactions between cells appear to be fundamental to tensional homeostasis, important questions remain. First, it is not known how the transmission of forces between cells impacts tensional homeostasis. Second, there is little understanding of how cells respond to external changes in their mechanical environment (e.g., mechanical stretch) after having initially achieved a steady state. In order to address these questions, this project will advance and apply a biomechanical imaging computational platform. The fundamental questions that can be answered using this technique will improve basic understanding of how cells respond to their mechanical environment. The biomechanical imaging methods and software will be distributed to any interested researcher in order to broadly disseminate this technique within the cellular mechanobiology and tissue engineering communities. In addition, graduate students and undergraduate students will be trained in a highly multidisciplinary environment and will mentor high school students for a six-week research experience.The biomechanical imaging computational platform maps intracellular stress distribution through simultaneous measurements of (1) traction forces that are transmitted by cells to the substrate and (2) intracellular displacements generated by externally applied stretch. In this project, the researchers will first improve the ability of the biomechanical imaging technique by using mitochondria as fiduciary markers in order to obtain more accurate maps of intracellular stress. The improved technique will then be used to address two fundamental questions. First, the impact of external stretch on tensional homeostasis of multicellular clusters will be investigated. This will be done using bovine aortic endothelial cells and primary human umbilical vein endothelial cells. Second, the system will be used to unravel the relevance of intercellular stress transmission on tensional homeostasis. This will include the investigation of the role of cell-cell adherens junctions and the impact of substrate stiffness on both cell-cell vs cell-matrix force transmission.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.

活细胞维持其内部机械应力以响应外部干扰的能力对于细胞和组织的正常生理功能以及对于防止各种疾病是必不可少的。 这就是所谓的张力稳态。 张力稳态的破坏是大多数晚期实体癌（癌）以及动脉硬化（动脉粥样硬化）和凝块形成（血栓形成）的标志。 虽然细胞之间的物理相互作用似乎是张力稳态的基础，但重要的问题仍然存在。 首先，尚不清楚细胞之间的力传递如何影响张力稳态。 其次，对细胞如何响应其机械环境中的外部变化（例如，机械拉伸）。 为了解决这些问题，本项目将提出并应用生物力学成像计算平台。 使用这种技术可以回答的基本问题将提高对细胞如何对其机械环境做出反应的基本理解。 生物力学成像方法和软件将分发给任何感兴趣的研究人员，以便在细胞机械生物学和组织工程界广泛传播这项技术。 此外，研究生和本科生将在高度多学科的环境中接受培训，并指导高中生进行为期六周的研究体验。生物力学成像计算平台通过同时测量（1）细胞传递到基底的牵引力和（2）外部施加拉伸产生的细胞内位移来绘制细胞内应力分布。 在该项目中，研究人员将首先通过使用线粒体作为可信标记来提高生物力学成像技术的能力，以获得更准确的细胞内应力图。 改进后的技术将用于解决两个基本问题。 首先，将研究外部拉伸对多细胞簇的张力稳态的影响。 这将使用牛主动脉内皮细胞和原代人脐静脉内皮细胞完成。 其次，该系统将被用来解开紧张的稳态细胞间的压力传递的相关性。 这将包括调查细胞-细胞粘附连接的作用和基底刚度对细胞-细胞与细胞-基质力传递的影响。该奖项反映了NSF的法定使命，并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，被认为值得支持。

项目成果

Focal adhesion displacement magnitude is a unifying feature of tensional homeostasis

焦点粘附位移大小是张力稳态的统一特征

• DOI: 10.1016/j.actbio.2020.06.043
• 发表时间: 2020
• 期刊: Acta Biomaterialia
• 影响因子: 9.7
• 作者: Xu, Han;Donegan, Stephanie;Dreher, Jordan M.;Stark, Alicia J.;Canović, Elizabeth P.;Stamenović, Dimitrije;Smith, Michael L.
• 通讯作者: Smith, Michael L.

Pattern Generation for Micropattern Traction Microscopy

微图案牵引显微镜的图案生成

• DOI: 10.3791/63628
• 发表时间: 2022
• 期刊: Journal of Visualized Experiments
• 作者: Bunde, Katie A.;Stamenović, Dimitrije;Smith, Michael L.
• 通讯作者: Smith, Michael L.

Reply to the ‘Comment on “Tensional homeostasis at different length scales” by J. Humphrey and C. Cyron, Soft Matter , 2022, 18 , DOI: 10.1039/D1SM01151K’

回复 J. Humphrey 和 C. Cyron 对“不同长度尺度下的张力稳态的评论”，Soft Matter，2022, 18，DOI: 10.1039/D1SM01151K —

• DOI: 10.1039/d1sm01495a
• 发表时间: 2022
• 期刊: Soft Matter
• 影响因子: 3.4
• 作者: Stamenović, Dimitrije;Smith, Michael L.
• 通讯作者: Smith, Michael L.

As the endothelial cell reorients, its tensile forces stabilize

随着内皮细胞重新定向，其张力稳定

• DOI: 10.1016/j.jbiomech.2020.109770
• 发表时间: 2020
• 期刊: Journal of biomechanics
• 影响因子: 2.4
• 作者: Stamenovic, D;Krishnan, R;Smith, ML
• 通讯作者: Smith, ML

Inflation instability in the lung: an analytical model of a thick-walled alveolus with wavy fibres under large deformations

• DOI: 10.1098/rsif.2021.0594
• 发表时间: 2021-10-13
• 期刊: JOURNAL OF THE ROYAL SOCIETY INTERFACE
• 影响因子: 3.9
• 作者: Jawde, Samer Bou;Karrobi, Kavon;Suki, Bela
• 通讯作者: Suki, Bela