Collaborative Research: Effects of Three-Dimensional Tissue Structure and Mechanics on Cellular Behavior

生物体中的细胞存在于蛋白质纤维和其他分子的网络中，称为细胞外基质，它提供结构支持和对细胞功能至关重要的化学输入。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如何排列和组织，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，人们仍未很好地了解其方式。该奖项支持基础研究，这些研究将提供必要的见解，了解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。一个新的细胞培养系统的结果导致细胞建立一个蛋白质基质具有控制形状和方向的蛋白质网络。该网格可以使用另一种新型工具进行拉伸和变形，并测量了单元对取向矩阵变形的响应。这项研究与正在进行的开发加速伤口愈合方法和工程人工组织修复受损器官的努力有关，因此这项工作的结果将具有广泛的影响，并为生物医学界提供关键资源。这一合作研究项目涉及来自多个领域的技术和见解，包括生物工程、物理学、微加工和细胞生物学，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粘附在许多重要的细胞功能中起着重要作用，这些功能对胚胎发育、成体组织稳态和疾病发病至关重要，包括细胞存活、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。该项目使用工程微组织来解决一个关键假设，即基质排列、常驻细胞的收缩活性、边界约束的几何形状和外部机械力的改变在机械转导机制中高度耦合，从而驱动细胞表型的变化。这些研究将确定这些因子如何调节成纤维细胞向活化的纤维化表型的转变，这在伤口愈合以及慢性纤维化和瘢痕形成中至关重要，但将更广泛地应用于对机械粘附线索有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. A novel cell culture system results leads cells to build a protein matrix that has controlled shape and orientation of the protein meshwork. The meshwork can be stretched and deformed using another novel tool and the response of the cells to deformation of the oriented matrix is measured. 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.