Cellular Response to Viscoelastic Substrates

过去十年的许多研究表明，细胞对周围组织的僵硬做出反应的方式是拉住它并感觉到它的僵硬，这一过程被称为机械转导。细胞使用这些机械转导信号来做出一系列关于生存、迁移和分化为不同类型细胞的决定。组织硬度的增加通常伴随着各种疾病，包括纤维性疾病和癌症。以前的研究表明，这些疾病可能是由僵硬改变引起的。然而，组织的另一个力学方面还没有得到相同程度的研究。人体内的组织是“粘弹性”的，这意味着它们的行为既像稠密的液体，也像可伸展的弹簧。虽然许多研究已经研究了改变“弹簧”成分的硬度对细胞的影响，但关于组织的粘性“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来分别改变细胞下表面的粘度和硬度，并确定细胞对每一组分的响应。这项工作将提高我们对细胞如何对环境做出反应的理解，这可能会在我们对人类健康的理解方面取得重大进展。过去二十年的研究令人信服地证明，细胞能够感知周围环境的机械特性，并对这种机械感觉做出重大决定，包括决定细胞的迁移、增殖、存活和分化。这些研究中的绝大多数都集中在细胞对基质硬度(或弹性模数)变化的机械响应上，并且都是在纯弹性基质上进行的。相比之下，人体内的大多数软组织表现出粘弹性行为，即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数(弹性分量)但显著不同损耗模数(粘性分量)的聚合物基板对。这些对的存储模数跨越了健康软组织到患病软组织的范围。假设增加损耗模数会产生类似于增加储能模数的效果；换句话说，在越来越粘稠的衬底上的细胞就像在更坚硬的衬底上一样做出反应。细胞形态、牵引力的产生、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。在这一步骤的基础上，将修改现有的细胞-衬底机械相互作用的计算模型，以开发一种潜在的机制来从机械上解释这种反应。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.