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周围组织的硬度做出反应，这一过程称为机械转导。细胞使用这些机械转导信号来做出关于存活、迁移和分化成不同细胞类型的许多决定。增加的组织硬度通常伴随各种疾病，包括纤维化疾病和癌症。 以前的研究表明，这些疾病可能是由改变僵硬。然而，组织的另一个机械方面尚未得到同等程度的研究。 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。虽然许多研究已经调查了如何改变“弹簧”组件的刚度影响细胞，但对组织的粘性“厚度”组件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，并确定细胞对每个组分的反应。这项工作将提高我们对细胞如何对其周围环境做出反应的理解，这可能会导致我们对人类健康的理解取得重大进展。过去20年的研究已经令人信服地证明，细胞能够感知周围环境的机械特性，并做出重大决定以响应这种机械感觉，包括关于细胞迁移，增殖，存活和分化的决定。 这些研究中的绝大多数都集中在细胞力学响应改变基板刚度（或弹性模量），并已进行了纯弹性基板。 相比之下，人体中的大多数软组织表现出粘弹性行为;也就是说，它们产生与应变的大小和速率成比例的响应力。 粘弹性组织中的粘性成分在驱动细胞的机械反应中起什么作用？ 为了回答这个问题，对聚合物基板，具有相似的储能模量（弹性组件），但显着不同的损耗模量（粘性组件）进行了研究。 这些对的储能模量跨越健康软组织到患病软组织的范围。 假设是增加损耗模量产生与增加储能模量类似的效果;换句话说，细胞在粘性增加的基质上的反应就像它们在更硬的基质上一样。 将量化细胞形态、牵引力产生、增殖、迁移和分化，以分离基质的粘性和弹性组分对细胞反应的影响。 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，以开发一个潜在的机制来解释这种反应mechanically.This奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.