Sticking around: Optimal cell adhesion patterning for energy minimization and substrate mechanosensing
Sticking around: Optimal cell adhesion patterning for energy minimization and substrate mechanosensing
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DOI：
10.1101/2020.08.17.253609
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发表时间：
2020-08
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通讯作者：
Josephine Solowiej-Wedderburn;Carina M. Dunlop
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作者：
Josephine Solowiej-Wedderburn;Carina M. Dunlop
细胞力转导，即细胞感知并响应其微环境的物理特性，被证明是理解跨生物学细胞行为的基础。组织硬度（杨氏模量）通常被视为关键控制参数，具有明确机械性能的生物工程凝胶已成为研究机械传导工具包的重要组成部分。然而，我们在这里使用机械细胞模型表明，细胞所经历的有效基底刚度不仅取决于基底的工程机械性能，而且还取决于细胞和基底之间粘附的特定排列。特别是，我们发现具有不同粘附模式的细胞可以经历两种不同的等效凝胶硬度，并且会产生相同的平均细胞变形。对于模拟实验观察到的粘着斑的小粘合剂贴片，我们证明观察到的粘附生长和伸长的动态可以通过能量考虑来解释。值得注意的是，我们显示了软质和硬质基材不同的粘着斑动力学，与报道的动力学一致，软质基材上的粘着斑生长不是优选的。同样，预计较少和较大的粘附优于较多和较小的粘附，这种效果通过随机点放置以及在这种情况下预测定性真实细胞形状的模拟而增强。该模型基于细胞和基质系统的连续弹性描述，并具有捕获细胞收缩性的主动应力分量。这项工作证明了在研究细胞硬度传感时考虑整个细胞-基质系统（包括粘附模式）的必要性，这对生物物理学和组织工程中的力传导控制具有影响。作者摘要 现在已知细胞能够感知其组织微环境的机械特性，并将其用作控制一系列行为的信号。在实验上，这种细胞力转导主要是使用精心设计的具有确定硬度的凝胶基质来研究的。在这里，我们使用将主动细胞收缩性与连续介质力学相结合的模型表明，细胞感知其环境的方式不仅取决于凝胶的硬度，还取决于粘附位点的空间图案。这样，如果粘附的位置不同，则细胞可以感受到两种刚度显着不同的凝胶是相似的。利用这一见解，我们证明，在坚硬的基材上，小粘附力的生长和伸长在能量上是有利的，但在软基材上情况并非如此。这与实验观察结果一致，即新生粘连仅成熟到坚硬基质上的稳定粘着斑（FA）位点，在那里它们也会生长和伸长。这些粘着斑（FA）一直是力转导工作的焦点。然而，我们的论文表明，根本需要考虑细胞和微环境组合系统，而不仅仅是关注单个 FA。
Cell mechanotransduction, in which cells sense and respond to the physical properties of their micro-environments, is proving fundamental to understanding cellular behaviours across biology. Tissue stiffness (Young’s modulus) is typically regarded as the key control parameter and bioengineered gels with defined mechanical properties have become an essential part of the toolkit for interrogating mechanotransduction. We here, however, show using a mechanical cell model that the effective substrate stiffness experienced by a cell depends not just on the engineered mechanical properties of the substrate but critically also on the particular arrangement of adhesions between cell and substrate. In particular, we find that cells with different adhesion patterns can experience two different gel stiffnesses as equivalent and will generate the same mean cell deformations. For small adhesive patches, which mimic experimentally observed focal adhesions, we demonstrate that the observed dynamics of adhesion growth and elongation can be explained by energy considerations. Significantly we show different focal adhesions dynamics for soft and stiff substrates with focal adhesion growth not preferred on soft substrates consistent with reported dynamics. Equally, fewer and larger adhesions are predicted to be preferred over more and smaller, an effect enhanced by random spot placing with the simulations predicting qualitatively realistic cell shapes in this case. The model is based on a continuum elasticity description of the cell and substrate system, with an active stress component capturing cellular contractility. This work demonstrates the necessity of considering the whole cell-substrate system, including the patterning of adhesion, when investigating cell stiffness sensing, with implications for mechanotransductive control in biophysics and tissue engineering. Author summary Cells are now known to sense the mechanical properties of their tissue micro-environments and use this as a signal to control a range of behaviours. Experimentally, such cell mechanotransduction is mostly investigated using carefully engineered gel substrates with defined stiffness. Here we show, using a model integrating active cellular contractility with continuum mechanics, that the way in which a cell senses its environment depends critically not just on the stiffness of the gel but also on the spatial patterning of adhesion sites. In this way, two gels of substantially different stiffnesses can be experienced by the cell as similar, if the adhesions are located differently. Exploiting this insight, we demonstrate that it is energetically favourable for small adhesions to grow and elongate on stiff substrates but that this is not the case on soft substrates. This is consistent with experimental observations that nascent adhesions only mature to stable focal adhesion (FA) sites on stiff substrates where they also grow and elongate. These focal adhesions (FAs) have been the focus of work on mechanotransduction. However, our paper demonstrates that there is a fundamental need to consider the combined cell and micro-environment system moving beyond a focus on individual FAs.