Conventional tissue engineering scaffolds have limited ability to undergo programmed changes in physical properties. Here we present a thermo-responsive and biocompatible tissue engineering scaffold prepared by electrospinning a shape memory polymer (SMP). SMPs have characteristics which allow them to be manipulated and fixed in a temporary shape and later recover back to their permanent shape on command. We hypothesized that a programmed change in scaffold architecture could control cell body orientation. To test this hypothesis, we uniaxially stretched an initially random mesh (the permanent state) and fixed it to a temporarily aligned mesh. After first seeding cells on the temporarily aligned mesh, we triggered a change in shape by increasing the temperature from 30°C to 37°C which resulted in the scaffold structure recovering back to its initial random structure. Alignment of cell bodies was quantified by two-dimensional fast Fourier transform (2D FFT) analysis of filamentous actin fibers. We found that before triggering a change in shape, cells aligned preferentially along the direction of fiber orientation. After the shape-memory-activated structure change, cells lost their preferential alignment. Shape-changing scaffolds based on this concept are anticipated to provide a powerful tool to study cell mechanobiology and increase tissue engineering scaffold functionality.