Cyclic stretching combined with cell-cell adhesion is sufficient for inducing cell intercalation.

Although the important role of cell intercalation within a collective has long been recognized particularly for morphogenesis, the underlying mechanism remains poorly understood. Here we investigate the possibility that cellular responses to cyclic stretching play a major role in this process. By applying synchronized imaging and cyclic stretching to epithelial cells cultured on micropatterned polyacrylamide (PAA) substrates, we discovered that uniaxial cyclic stretching induces cell intercalation along with cell shape change and cell-cell interfacial remodeling.

Cyclic stretching-induced epithelial cell reorientation is driven by microtubule-modulated transverse extension during the relaxation phase.

Many types of adherent cells are known to reorient upon uniaxial cyclic stretching perpendicularly to the direction of stretching to facilitate such important events as wound healing, angiogenesis, and morphogenesis. While this phenomenon has been documented for decades, the underlying mechanism remains poorly understood. Using an on-stage stretching device that allowed programmable stretching with synchronized imaging, we found that the reorientation of NRK epithelial cells took place primarily during the relaxation phase when cells underwent rapid global retraction followed by extension transverse to the direction of stretching.