MEMS platform for study of dynamic cell-cell interaction

描述(由申请人提供)：由于分离的肝细胞中肝脏特异性功能的关键决定因素尚不清楚，目前基于细胞的肝病治疗进展仍然缓慢且高度经验性。异型(肝细胞/非实质)细胞-细胞接触在胚胎发育和体外培养中都能诱导肝细胞分化功能。 然而，由于目前实验技术的局限性，细胞间相互作用影响分化的分子机制和这种反应的动力学都还没有被阐明。MEMS(微电子机械系统)技术的最新发展使得通过使用集成电路微制造方法来制造具有微观尺寸的复杂机械设备成为可能。利用这项技术，这项拟议的研究旨在利用一个微型制造平台来研究肝细胞对细胞与非实质细胞接触的动态反应，该平台使用户能够在不同的感兴趣的时间点启动和中断异型接触。具体的问题包括异型黏附连接的形成和肝脏特异性基因表达的启动之间的相关性，维持分化功能的持续信号的必要性，以及相互信号在非实质细胞诱导能力中的作用。更好地了解肝细胞分化的机制和动力学，对肝脏发育和肝组织工程具有重要意义。此外，该平台还将在许多不同器官系统的细胞-细胞相互作用的研究中找到广泛的用途。

DESCRIPTION (provided by applicant): Progress in cell-based therapies for liver disease currently remains slow and highly empirical due to the fact that the key determinants of liver-specific function in isolated hepatocytes remain unknown. Heterotypic (hepatocyte/non-parenchymal) cell-cell contact has been shown to induce differentiated function in hepatocytes both in embryogenesis and in vitro. However, neither the molecular mechanism by which cell-cell interactions impact differentiation nor the dynamics of this response have been elucidated, in part, due to the limitations of current experimental techniques. The recent development of MEMS (microelectromechanical systems) technology has enabled the creation of complex mechanical devices with microscopic dimensions through the use of integrated circuit microfabrication methods. Taking advantage of this technology, the proposed research intends to study the dynamics of hepatocyte response to cell-cell contact with non-parenchymal cells using a microfabricated platform that enables the user to initiate and disrupt heterotypic contact at various time points of interest. The specific questions addressed will be the correlation between the formation of heterotypic adherents junctions and the onset of liver-specific gene expression, the necessity of continuous signaling to maintain differentiated functions, and the role of reciprocal signaling on the inductive capability of non-parenchymal cells. Better understanding of the mechanisms and dynamics of hepatocyte differentiation has important implications in liver development and hepatic tissue engineering. In addition, this platform will also find broad utility in the study of cell-cell interactions in many different organ systems.