Directing Cellular Interactions and Organization with Synthetic Adhesion Receptors

Cellular adhesion molecules have evolved to control an array of intracellular signaling functionalities that are critical to the regulation of multicellular organisms. In order to design artificial multicellular systems capable of complex organization and behavior, we have engineered a toolkit of synthetic cellular adhesion molecules with programmable extracellular recognition domains that activate endogenous signaling. This engineering strategy enables control of both the manner of extracellular engagement (e.g. homophilic or heterophilic) and choice of intracellular signaling program. For example, some of these synthetic receptors mediate tight cell-cell interactions via cytoskeletal reorganization, while others facilitate receptor enrichment through the recruitment of scaffold proteins. Using these receptors, we explore the interplay between extracellular affinity and intracellular signaling output in dictating cellular adhesion strength. Moreover, we examine how introducing asymmetric signaling interfaces not present in nature impacts cell-cell adhesion. We then apply this system to form multicellular structures with precise cellular architecture and defined compartmentalization. Lastly, we integrate synthetic adhesion to modulate native cell interactions from endogenous adhesion molecules. We are presently employing this new capability to investigate the relationship between cellular patterning and tissue function and to design T cells capable of custom tissue trafficking.