Cellular Response to Viscoelastic Substrates

过去十年的许多研究表明，细胞通过拉动周围组织并感知其硬度来对其做出反应，这一过程被称为机械转导。细胞利用这些机械转导信号做出一系列有关生存、迁移和分化为不同细胞类型的决定。组织僵硬度增加通常伴随着各种疾病，包括纤维化疾病和癌症。先前的研究表明，这些疾病可能是由僵硬改变引起的。然而，组织的另一个机械方面还没有研究到同样的程度。人体组织是“粘弹性的”，这意味着它们的行为既像粘稠的液体，又像可拉伸的弹簧。虽然许多研究已经研究了改变“弹簧”成分的刚度如何影响细胞，但对组织的粘性“厚度”成分的影响的研究要少得多。在这项研究中，将探索使用新型聚合物分别改变细胞下表面的粘度和刚度，并确定细胞对每种成分的反应。这项工作将提高我们对细胞如何对周围环境作出反应的理解，这可能会使我们对人类健康的理解取得重大进展。过去二十年的研究令人信服地表明，细胞能够感知周围环境的机械特性，并根据这种机械感觉做出重大决定，包括有关细胞迁移、增殖、生存和分化的决定。这些研究绝大多数集中在改变基质刚度（或弹性模量）的细胞力学反应上，并且在纯弹性基质上进行。相反，人体内的大多数软组织表现出粘弹性行为；也就是说，它们产生的响应力与应变的大小和速率成正比。粘弹性组织的粘性成分在驱动细胞机械反应中起什么作用？为了回答这个问题，研究了具有相似存储模量（弹性模量）但明显不同损失模量（粘性模量）的聚合物基片对。这些对的存储模组跨越了健康到病变软组织的范围。假设增加损耗模量与增加存储模量产生相似的效果；换句话说，在黏度越来越高的基质上，细胞的反应就像在更硬的基质上一样。细胞形态、牵引力产生、增殖、迁移和分化，以分离基质的粘性和弹性成分对细胞反应的影响，将被量化。基于这一步骤，现有的细胞-基质机械相互作用的计算模型将被修改，以开发一种潜在的机制来机械地解释这种反应。该奖项反映了美国国家科学基金会的法定使命，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。

Many studies over the past decade have demonstrated that cells respond to the stiffness of the surrounding tissue by pulling on it and sensing the stiffness, a process known as mechanotransduction. Cells use these mechanotransduction signals to make a host of decisions regarding survival, migration, and differentiation into different cell types. Increased tissue stiffness often accompanies various diseases including fibrotic diseases and cancer. Previous studies suggest that these diseases may be driven by altered stiffness. However, there is another mechanical aspect of tissues that has not been studied to the same degree. Tissues in the human body are “viscoelastic”, meaning that they behave like both a thick liquid and a stretchable spring. While many studies have investigated how changing the stiffness of the “spring” component affects cells, there have been far fewer studies of the effects of the viscous “thickness” component of the tissue. In this research, the use of novel polymers to separately change the viscosity and the stiffness of the surface under cells and determine the cellular responses to each component will be explored. This work will improve our understanding of how cells respond to their surroundings, which could lead to significant advances in our understanding of human health. Studies from the past two decades have convincingly convincingly that cells are able to sense the mechanical properties of their surroundings and make major decisions in response to this mechanosensation, including decisions regarding cell migration, proliferation, survival, and differentiation. The vast majority of these studies have focused on the cellular mechanoresponse to changing substrate stiffness (or elastic modulus) and have been conducted on purely elastic substrates. In contrast, most soft tissues in the human body exhibit viscoelastic behavior; that is, they generate responsive force proportional to both the magnitude and rate of strain. What role does the viscous component of viscoelastic tissue play in driving the cellular mechanoresponse? To answer this question, pairs of polymer substrates that have similar storage moduli (elastic component) but significantly different loss moduli (viscous component) are investigated. The storage moduli for these pairs spans the range of healthy to diseased soft tissue. The hypothesis is that increasing loss modulus produces similar effects to increasing storage modulus; in other words, cells on an increasingly viscous substrate respond as if they are on a stiffer substrate. Cell morphology, traction force generation, proliferation, migration, and differentiation to isolate the effects of viscous and elastic components of the substrate on cellular responses will be quantified. Based on that step, an existing computational model of cell-substrate mechanical interactions will be modified to develop a potential mechanism to explain this response mechanistically.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.