| The long-term sustenance of functional hepatocytes in intimate contact with biomaterial scaffolds is central to the success of cell-based therapies for liver failure. Although cell-cell contact has been shown to be a critical parameter in the control of hepatocellular proliferation and function in cultures (1, 2), the role of molecular mediators of cell-cell contact has not been understood well enough to be applied toward the design of culture configurations. This work is concerned with the elucidation of the molecular basis for cell functional and proliferative regulation via cell-cell contacts and the systematic application of contact-mediating molecules with a view to develop biomimetic substrates for tissue engineering.; Specifically, this study investigates the effects on hepatocyte functional and proliferative behavior of the cell-cell adhesion molecule E-cadherin, which has been implicated in the regulation of growth and differentiation in several cell types (3–5). The role of cadherin in the determination of hepatocyte differentiated function is first developed for presentation of cadherins at their native location, the lateral domains of cell membranes, and then extended to hepatocyte growth and function in response to acellular display of cadherins. We demonstrate that cell-presented cadherins induce liver-specific function, but only at high levels of cadherin presentation. Importantly this effect must be due to cadherin signaling activity, as cell morphology and cell number were held constant in this coculture based model system. In contrast, acellular cadherins introduced to the upper domain induce an increase in hepatocyte proliferation and a decrease in liver-specific function, an effect that dominated when acellular cadherins were applied to previously functional cocultures involving cell-presented cadherins. Further mechanistic analysis revealed that acellular cadherins cause degradation of endogenous hepatocellular cadherins and disruption from cell-cell junctions of cadherins and their main signaling messenger, β-catenin, resulting in changes in gene expression. Overall, this study demonstrates the modulation of hepatocyte proliferation and differentiation by cellular and acellular cadherins. |
