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.
| Hui, Elliot E; Li, Chun; Agrawal, Amit et al. (2014) A Macro-to-Micro Interface for the Control of Cellular Organization. J Microelectromech Syst 23:391-397 |
| March, Sandra; Hui, Elliot E; Underhill, Gregory H et al. (2009) Microenvironmental regulation of the sinusoidal endothelial cell phenotype in vitro. Hepatology 50:920-8 |
