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性能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，刚性，量化的弹性模量，决定成纤维细胞的运动率，强度与细胞拉在其基板上，和表达水平的基因产物，如特定的整合素，肌动蛋白的亚型，或类中间丝。也许最重要的是，改变的刚性还导致功能或优先生长的特定变化，例如肝星状细胞和星形胶质细胞的激活与刚性增加，神经元突起延伸和分支增加与刚性降低，乳腺上皮从正常到异常结构的变化，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，例如所涉及的粘附受体的类型或化学刺激的量和性质，但在其他情况下，机械效应优于化学信号传导，因为当细胞生长时，导致特异性分化模式或导致细胞活化的可溶性刺激物不能发挥其作用，所述可溶性刺激物对刚性基质上的细胞是有效的更柔软的材料。不同细胞类型响应的刚性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内，体外观察到的显著刚性范围与原代细胞来源的组织的刚性相匹配。该项目的目标是测试的假设，即矩阵刚度影响细胞功能独立的化学信号，细胞类型的特定机械响应可用于设计材料的特定的生物用途，并开发更好的方法来研究材料性能对细胞结构和功能的影响。细胞外材料硬度的影响可能与疾病过程相关，如纤维化和肿瘤形成，其中宏观硬度变化在病理状态下是明显的。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.