Mechanical control of cell growth and differentiation

描述(申请人提供)：细胞生长的表面或三维基质的机械性质对许多细胞类型的形态、转录程序和功能有重要影响。最近的研究表明，刚性决定了成纤维细胞的运动率、细胞对其底物的拉力以及特定整合素、肌动蛋白的异构体或中间细丝等基因产物的表达水平。也许最重要的是，僵硬改变还会导致特定的功能或优先生长的变化，如肝星状细胞和星形胶质细胞的激活增加了刚性，神经元突起伸展和分支增加而刚性降低，乳腺上皮结构从正常到异常变化，以及间充质干细胞的分化途径。在某些情况下，机械效应的大小可以通过其他因素来改变，如所涉及的黏附受体的类型或化学刺激的数量和性质，但在其他情况下，力学的影响主导于化学信号，因为当细胞生长在较软的材料上时，导致特定分化模式或细胞激活的可溶刺激无法发挥其作用。不同类型的细胞对硬度的定量水平也可能至少相差一个数量级，在有限的可用数据中，体外观察到的显著硬度范围与原始细胞来源的组织的硬度相匹配。该项目的目标是验证这样的假设，即基质刚性独立于化学信号影响细胞功能，细胞类型的特定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。细胞外物质硬度的影响可能与纤维化和肿瘤形成等疾病过程有关，在这些疾病过程中，病理状态下宏观硬度变化明显。细胞生长材料的力学性能对细胞的形态和功能有着至关重要的影响。我们建议确定特定细胞功能的最佳硬度，并设计柔软的生物相容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.