Control of receptor-mediated cell behavior using synthetic polymers

Summary form only received as follows: Virtually every aspect of cell behavior is governed at some level by interactions of receptor molecules on the cell surface with ligands in the extracellular environment. Molecular components involved in activation of receptor-mediated signaling pathways which culminate in cell migration, differentiation, and growth are being identified at a rapid rate. Much overlap exists in signaling pathways activated by distinct classes of receptors; for example, ligand activation of growth factor receptors influences integrin-mediated process of migration while integrin ligation is required for growth factor-induced proliferation of many cell types. Several common intracellular signaling molecules are activated by both integrins and growth factors. How does the cell take information from such overlapping stimuli and process it to achieve different responses? In addition to the specific identity of molecules involved, the overall context of ligand presentation-relative concentrations, spatial organization, and kinetics-must be considered to understand how a cell integrates stimuli to achieve a precise response. In order to parse how these factors contribute to the overall integrated cell response, the author is developing approaches in which key variables can be systematically controlled by a combination of biochemical and physical means. This paper focuses on the physical aspects of this approach-designing new polymeric materials which can be applied to both tissue engineering and to fundamental studies of receptor-mediated phenomena. A specific interest is controlling signaling by the epidermal growth factor receptor (EGFR). For example, the author has shown that mEGF stimulates both DNA synthesis and cytoskeletal changes in primary hepatocytes when tethered covalently to the culture substrate so that internalization is inhibited, and that EGF can serve as either a stimulatory or inhibitory regulator of cell migration speed depending on the cell-substrate adhesion characteristics. The author is adapting these basic findings to the design of 3D scaffold materials for tissue engineering, including surface modification of degradable polymers as well as a new enzymatically crosslinked hydrogels for cell encapsulation