Collaborative Research: The Effects of Extracellular Matrix Alignment on Cellular Mechanotransduction in 3D Architectures

活着的生物体中的细胞存在于蛋白质纤维和其他分子的网络中，被称为细胞外基质，它提供了对细胞功能至关重要的结构支持和化学输入。细胞外基质的结构特性在很大程度上取决于这些蛋白质纤维的排列和组织方式，以及这些结构的变化，并与许多人类疾病的进展有关，但在许多情况下，人们仍然不太清楚这些变化的方式。该奖项支持基础研究，这些研究将为细胞外基质的组织和由此产生的机械特性如何影响和控制细胞的正常和病理行为提供必要的见解。这项研究与正在进行的开发加速伤口愈合的方法和工程人造组织修复受损器官的努力有关，因此这项工作的结果将产生广泛的影响，并为生物医学界提供关键资源。这一合作研究项目涉及生物工程、物理、微制造和细胞生物学等多个领域的技术和见解，并提供培养下一代科学家和工程师所需的跨学科培训。细胞与细胞外基质的黏附在许多对胚胎发育、成人组织动态平衡和疾病发病机制至关重要的关键细胞功能中发挥着重要作用，包括细胞生存、迁移、增殖和分化。然而，很少有系统允许控制并因此研究纤维细胞外基质结构对细胞功能的特定影响。这个项目使用工程化的微组织来解决这一关键假设，即基质排列的变化、驻留细胞的收缩活动、边界约束的几何形状和外部机械力在一个将驱动细胞表型变化的机械转导机制中高度耦合。这些研究将确定这些因素如何调节成纤维细胞向激活的纤维化表型的转变，这种表型在伤口愈合以及慢性纤维化和瘢痕形成中是关键的，但将更广泛地适用于对机械粘连信号做出反应的许多细胞类型。

Cells in living organisms reside in a meshwork of protein fibers and other molecules, termed the extracellular matrix, which provides both structural support and chemical inputs that are critical to the functioning of the cells. The structural properties of the extracellular matrix are largely determined by how these protein fibers are aligned and organized, and changes in these structures and are associated with the progression of many human diseases, but in ways that in many cases are still not well understood. This award supports fundamental research that will provide needed insights into how the organization and resulting mechanical properties of the extracellular matrix influence and control both the normal and pathological behavior of cells. This research is relevant to ongoing efforts to develop methods to speed wound healing, and to engineer artificial tissues to repair damaged organs, and so the results from this work will have broad impact and provide critical resources to the biomedical community. This collaborative research program involves techniques and insights drawn from several fields, including bioengineering, physics, microfabrication, and cell biology, and provides interdisciplinary training needed to prepare the next generation of scientists and engineers.The adhesion of cells to the extracellular matrix plays a major role in many critical cellular functions important to embryonic development, adult tissue homeostasis, and disease pathogenesis, including cell survival, migration, proliferation, and differentiation. Yet, there have been few systems that allow control and therefore study the specific effects of fibrillar extracellular matrix architecture on cell function. This project use engineered microtissues to address the key hypothesis that alterations in the alignment of matrix, contractile activity of resident cells, geometry of boundary constraints, and external mechanical forces are highly coupled in a mechanotransduction machinery that will drive changes in cellular phenotype. These studies will determine how these factors regulate the transition of fibroblasts to an activated, fibrotic phenotype that is critical in wound healing as well as chronic fibrosis and scarring, but will apply more broadly to many cell types that response to mechanoadhesive cues.