Engineering the Hepatocyte Differentiation–Proliferation Balance by Acellular Cadherin Micropresentation

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Abstract
The successful development of bioartificial and cell-based liver support systems relies on the identification of molecular mechanisms controlling the balance between hepatocellular proliferation and differentiation. Although a definitive function-inductive role for the cell–cell adhesion molecule, E-cadherin, was established through lateral cadherin–cadherin engagement in hepatocyte cocultures (Brevia, T.A., and Moghe, P.V. Biotechnol. Bioeng. 76, 295, 2001), the roles of other modes of cadherin presentation are not well understood. Further, alternative cadherin display configurations promoting cell growth/proliferative pathways, a major requisite for sustainable engineered tissues, remain to be identified. In this report, we employed protein A-functionalized polymeric microsphere substrates that specifically bound self-dimerizing cadherin-IgG/Fc fusion chimeras via their Fc regions, thereby orienting them outward for active adhesion, and presented the E-cadherin chimeras basally to cultured rat hepatocytes to study the effects of cadherin display on cell proliferative potential and differentiated function. In contrast to the previously documented function-inductive roles of laterally expressed cadherin, basal acellular cadherin presentation resulted in an increase in hepatocyte DNA synthesis and cell divisions, accompanied by a decrease in the expression of a key marker of liver-specific function, albumin message levels. Next, we probed the relative effect of basal exogenous display of acellular cadherins on the inductive phase of differentiation within hepatocyte cocultures with cadherin-expressing L929 cells. When acellular cadherins were applied to hepatocyte cocultures involving chaperone cell-mediated cadherin presentation, the previously reported function-inductive effects of cadherins on hepatocyte function were reversed, resulting in lower levels of albumin and urea secretion indicating a dominance of acellular cadherin effects. Our results demonstrate that cadherins are important regulators of the balance between hepatocyte differentiation and proliferation, and furthermore that the direction of balance shift may be dependent on the method of cadherin presentation. Thus, the geometric display of cadherin could be a potential parameter to switch hepatocyte functional–proliferative balance and may aid in customizing scaffolds for regulating hepatic tissue dynamics.

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