Heterogeneity Profoundly Alters Emergent Stress Fields in Constrained Multicellular Systems
Heterogeneity Profoundly Alters Emergent Stress Fields in Constrained Multicellular Systems
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DOI：
10.1016/j.bpj.2019.11.018
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发表时间：
2020-01-07
影响因子：
3.4
通讯作者：
Billiar, Kristen L.
中科院分区：
文献类型：
--
作者：
Goldblatt, Zachary E.;Choshali, Habibeh Ashouri;Billiar, Kristen L.
在多细胞系统中，细胞间的力传递产生的应力场越来越被认为是细胞命运的主要决定因素。目前用于计算细胞单层内应力的分析和数值模型假定细胞具有均匀的收缩和力学特性；然而，在受约束的组织中，细胞的行为因区域而异。在这里，我们展示了异质细胞属性对引导细胞表型和凋亡的应力场的影响。使用环形微图案，我们测量了与细胞机械应力相关的生物物理指标。然后，我们使用有限元收缩模型和单层应力显微镜计算了细胞层应力分布。与以前的研究一致，从细胞层的中心到边缘，细胞的铺展面积、排列和牵引力增加，而凋亡活性减少。这些指标的分布清楚地表明，中心区域的细胞应力较低，而图案外围的细胞应力较高。然而，当假定均匀的收缩和力学性能时，计算模型预测了相反的趋势。在我们的模型中，利用基于实验测量的生物物理参数的细胞层非均匀收缩系数和弹性模量值，我们计算了中心区域的低细胞应力和外围区域的高各向异性应力，这与生物统计学相一致。这些结果清楚地表明，在汇合后受限的多细胞系统中，细胞收缩和硬度均匀的常见假设被打破。这项工作强调了在从集体细胞行为中估计紧急应力场时，结合细胞力学性质的区域差异的重要性。
Stress fields emerging from the transfer of forces between cells within multicellular systems are increasingly being recognized as major determinants of cell fate. Current analytical and numerical models used for the calculation of stresses within cell monolayers assume homogeneous contractile and mechanical cellular properties; however, cell behavior varies by region within constrained tissues. Here, we show the impact of heterogeneous cell properties on resulting stress fields that guide cell phenotype and apoptosis. Using circular micropatterns, we measured biophysical metrics associated with cell mechanical stresses. We then computed cell-layer stress distributions using finite element contraction models and monolayer stress microscopy. In agreement with previous studies, cell spread area, alignment, and traction forces increase, whereas apoptotic activity decreases, from the center of cell layers to the edge. The distribution of these metrics clearly indicates low cell stress in central regions and high cell stress at the periphery of the patterns. However, the opposite trend is predicted by computational models when homogeneous contractile and mechanical properties are assumed. In our model, utilizing heterogeneous cell-layer contractility and elastic moduli values based on experimentally measured biophysical parameters, we calculate low cell stress in central areas and high anisotropic stresses in peripheral regions, consistent with the biometrics. These results clearly demonstrate that common assumptions of uniformity in cell contractility and stiffness break down in postconfluence confined multicellular systems. This work highlights the importance of incorporating regional variations in cell mechanical properties when estimating emergent stress fields from collective cell behavior.