Competition Between Contractility and Surface Tension in Collective Cell Migration

集体细胞迁移中收缩性和表面张力之间的竞争

• 批准号: 1660703
• 负责人: Jacob Notbohm
• 金额: $ 34.5万
• 依托单位: University of Wisconsin-Madison
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1660703&HistoricalAwards=false
• 关键词: Competition; Between; Contractility; Surface; Tension

Biological cells migrate in groups both during healthy life and also during diseases during tissue changes ranging from wound repair to cancer progression. The migration can restore normal function of damaged tissue, as in wound repair, or further the spread of disease, as in a spreading cancer. In both wound healing and cancer, it is typical for cells to migrate together where each cell's motion depends its own active contractile forces and its interaction with neighbors. The resulting cellular motions can vary dramatically--from a solid-like state, where each cell remains close to its neighbors, to a fluid-like state, where each cell freely migrates past its neighbors. The transition between solid-like and fluid-like migration occurs in both wound healing and cancer invasion and its causes remain unclear. Theoretical models have predicted that the transition depends on the adhesion molecules between neighboring cells, and, counterintuitively, that greater adhesion causes a more fluid-like behavior. This prediction is complicated by the fact that some molecules associated with cell-cell adhesion also cause cells to contract and pull against their neighbors. The work will experimentally examine the competing roles of adhesion and contraction on collective migration, thereby clarifying our understanding of collective migration and providing new insights into how the migration may be promoted in wound healing or reduced during cancer progression. The PI will recruit undergraduate students from underrepresented groups in science and engineering through the Summer Undergraduate Research Experience (SURE) program in the College of Engineering at UW-Madison. Through the SURE program, these students will gain research experience and will be encouraged to pursue graduate studies.This research will test the hypothesis that the solid-to-fluid transition results from a balance between the active contractile tension inside each cell and the adhesive surface energy at each cell-cell interface. To quantify intercellular adhesion, this project will use a mechanically rigorous definition, the surface tension. To quantify contraction, it will use the contractile stress within each cell. Surface tension and contractile stress will be modulated by using pharmacological inhibitors and transfections of appropriate signaling pathways, and they will be measured by using state-of-the art optical microscopy and quantitative image analysis. The first objective of this research will reveal how the intracellular surface tension results from the balance between the actomyosin contraction in each cell's cortex and the adherens junctions at each cell-cell interface. The second objective will investigate how contractility and surface tension together regulate the multicellular motion. The resulting data will give a complete account of the mechanics of collective cellular motion, and thus they will provide an empirical basis for testing theories for the mechanisms of collective migration.

在健康生活期间以及在从伤口修复到癌症进展等组织变化期间的疾病期间，生物细胞都会成群迁移。这种迁移可以恢复受损组织的正常功能，如伤口修复，或进一步扩散疾病，如扩散的癌症。在伤口愈合和癌症中，细胞通常会一起迁移，其中每个细胞的运动取决于其自身的主动收​​缩力及其与邻近细胞的相互作用。由此产生的细胞运动可能会发生巨大变化——从每个细胞保持靠近其邻居的固体状状态，到每个细胞自由迁移经过其邻居的流体状状态。固体状和液体状迁移之间的转变发生在伤口愈合和癌症侵袭中，其原因仍不清楚。理论模型预测，这种转变取决于相邻细胞之间的粘附分子，并且与直觉相反，更大的粘附会导致更像流体的行为。 由于一些与细胞间粘附相关的分子也会导致细胞收缩并拉扯相邻细胞，这一事实使这一预测变得复杂。这项工作将通过实验研究粘附和收缩对集体迁移的竞争作用，从而澄清我们对集体迁移的理解，并为如何促进伤口愈合或在癌症进展过程中减少迁移提供新的见解。 PI 将通过威斯康星大学麦迪逊分校工程学院的暑期本科生研究体验 (SURE) 项目，从科学和工程领域的代表性不足的群体中招收本科生。通过 SURE 项目，这些学生将获得研究经验，并被鼓励继续攻读研究生。这项研究将检验这样一个假设：固体到液体的转变是由每个细胞内部的主动收缩张力和每个细胞-细胞界面的粘附表面能之间的平衡引起的。为了量化细胞间粘附，该项目将使用机械上严格的定义，即表面张力。为了量化收缩，它将使用每个细胞内的收缩应力。表面张力和收缩应力将通过使用药理学抑制剂和适当信号通路的转染来调节，并且将通过使用最先进的光学显微镜和定量图像分析来测量它们。这项研究的第一个目标将揭示细胞内表面张力是如何由每个细胞皮质中的肌动球蛋白收缩与每个细胞-细胞界面上的粘附连接之间的平衡产生的。第二个目标将研究收缩性和表面张力如何共同调节多细胞运动。由此产生的数据将完整地解释集体细胞运动的机制，从而为检验集体迁移机制的理论提供经验基础。

项目成果

Coordinated tractions increase the size of a collectively moving pack in a cell monolayer

协调的牵引力增加了单层细胞中集体移动包的尺寸

• DOI: 10.1016/j.eml.2021.101438
• 发表时间: 2021
• 期刊: Extreme Mechanics Letters
• 影响因子: 4.7
• 作者: Saraswathibhatla, Aashrith;Henkes, Silke;Galles, Emmett E.;Sknepnek, Rastko;Notbohm, Jacob
• 通讯作者: Notbohm, Jacob

Two-Dimensional Culture Systems to Enable Mechanics-Based Assays for Stem Cell-Derived Cardiomyocytes

• DOI: 10.1007/s11340-019-00473-8
• 发表时间: 2019-11-01
• 期刊: EXPERIMENTAL MECHANICS
• 影响因子: 2.4
• 作者: Notbohm, J.;Napiwocki, B. N.;Crone, W. C.
• 通讯作者: Crone, W. C.

Topological defects in the mesothelium suppress ovarian cancer cell clearance.

• DOI: 10.1063/5.0047523
• 发表时间: 2021-09
• 期刊: APL bioengineering
• 影响因子: 6
• 作者: Zhang J;Yang N;Kreeger PK;Notbohm J
• 通讯作者: Notbohm J

Tractions and Stress Fibers Control Cell Shape and Rearrangements in Collective Cell Migration

牵引和应力纤维控制集体细胞迁移中的细胞形状和重排

• DOI: 10.1103/physrevx.10.011016
• 发表时间: 2020
• 期刊: Physical Review X
• 影响因子: 12.5
• 作者: Saraswathibhatla, Aashrith;Notbohm, Jacob
• 通讯作者: Notbohm, Jacob

Spatiotemporal force and motion in collective cell migration

• DOI: 10.1038/s41597-020-0540-5
• 发表时间: 2020-06-24
• 期刊: SCIENTIFIC DATA
• 影响因子: 9.8
• 作者: Saraswathibhatla, Aashrith;Galles, Emmett E.;Notbohm, Jacob
• 通讯作者: Notbohm, Jacob