Mechanical control of cell growth and differentiation

描述（由申请人提供）：细胞生长的表面或三维基质的机械特性对许多细胞类型的形态、转录程序和功能具有关键影响。最近的研究表明，弹性模量量化的刚性决定了成纤维细胞的运动速率、细胞拉底物的强度，以及特定整合素、肌动蛋白同工型或中间纤维类等基因产物的表达水平。也许最重要的是，刚性的改变也会导致功能或优先生长的特定变化，例如，刚性增加的肝星状细胞和星形胶质细胞的激活，刚性降低的神经元过程延伸和分支增加，乳腺上皮从正常到异常结构的变化，以及间质干细胞的分化途径。在某些情况下，机械效应的大小可以被其他因素所改变，如所涉及的粘附受体的类型或化学刺激的数量和性质，但在其他情况下，机械效应优于化学信号传导，因为可溶性刺激导致特定的分化模式或细胞激活，这些对坚硬基质上的细胞有效，当细胞生长在较软的材料上时，它们无法发挥作用。不同细胞类型响应的刚度的定量水平也可以相差至少一个数量级，并且在有限的可用数据中，在体外观察到的显著刚度范围与原代细胞来源于的组织的刚度相匹配。该项目的目标是测试基质刚性独立于化学信号影响细胞功能的假设，细胞类型特定的机械反应可用于设计特定生物用途的材料，并开发更好的方法来研究材料特性对细胞结构和功能的影响。细胞外物质刚度的影响可能与疾病过程有关，如纤维化和肿瘤形成，其中宏观刚度变化在病理状态下是明显的。细胞生长的材料的机械性能对细胞的形态和功能有重要的影响。我们建议确定特定细胞功能的最佳刚度，并设计柔软的生物相容性材料来支持细胞生长和功能。

DESCRIPTION (provided by applicant): The mechanical properties of surfaces or three dimensional matrices on which or in which cells grow have a critical influence on the morphology, transcriptional program, and function of many cell types. Recent studies show that rigidity, as quantified by the elastic modulus, determines the rates of fibroblast motility, the strength with which cells pull on their substrate, and the level of expression of such gene products as specific integrins, isoforms of actin, or class of intermediate filament. Perhaps most significantly, altered rigidity also leads to specific changes in function or preferential growth, such as activation of hepatic stellate cells and astrocytes with increased rigidity, increased neuronal process extension and branching with decreased rigidity, change from normal to abnormal structures in breast epithelia, and the differentiation pathway of mesenchymal stem cells. In some cases the magnitude of the mechanical effect can be modified by other factors such as the type of adhesion receptor involved or the amount and nature of chemical stimuli, but in other cases, the effect of mechanics dominates over chemical signaling, in that soluble stimuli that lead to specific differentiation patterns or to cell activation that are potent for cells on rigid substrates fail to exert their effect when cells are grown on softer materials. The quantitative level of rigidity to which different cell types respond can also differ by at least one order of magnitude, and within the limited data available, the significant stiffness range observed in vitro matches the rigidity of the tissue from which the primary cells derive. The goals of this project are to test the hypothesis that matrix rigidity affects cell function independently of chemical signaling, that cell-type specific mechanical responses can be used to design materials for specific biological uses, and to develop better methods by which to study the effects of material properties on cell structure and function. Effects of extracellular material stiffness may be relevant to disease processes such as fibrosis, and tumor formation in which macroscopic stiffness changes are evident in the pathologic state. The mechanical properties of the materials in which cells grow have a critical influence on the morphology and function of cells. We propose to determine optimal stiffness for specific cell functions and design soft biocompatible materials to support cell growth and function.