Cells sense and interact with their environment using chemical and physical signals including

cell-matrix and cell-cell contacts. These signals often control the global and local shapes of cells

by modulating the cytoskeletal structure, but can the local shape alone provide functionally

relevant information? We hypothesize that physiologically relevant shapes can encode

information needed to maintain the cell in a differentiated state. This conjecture raises two

follow-on questions: (i) how is the information stored in cell shape retrieved; and (ii) how does

this information contribute to cellular phenotype? Theoretical analyses, based on reaction-

diffusion system and optimal control theory, indicate that information from cell shape can be

resolved from physical signals and uniquely retrieved by adopting shapes with distinct surface-

to-volume relationships. We used microfabricated 3-D biomimetic chips to validate the

predictions from the theoretical analyses. We constructed single-cell patterns representing

simplified versions of the in vivo morphology of two cell types, kidney podocytes, and smooth

muscle cells. In both types, cells in the shapes showed marked phenotypic changes, as measured

by expression levels of physiologically important proteins and localization of these proteins to

the appropriate subcellular compartment. Using differential proteomics and functional ablation

assays, we found that β 3 integrin and its binding partners from the ezrin-radixin-moesin (ERM)

family are involved in the transduction of shape signals. These observations indicate that

physiological cell shape, including local specialization, embodies information obtained

during the development, which is utilized to maintain the cell in the differentiated state.