Nuclear Deformation and Stiffness-Dependent Traction Force Generation Dictate the Migration of Cells under Confinement.

Cells need to migrate through confined spaces during processes such as embryo development and cancer metastasis. However, the fundamental question of how confinement size and surrounding rigidity collectively regulate the migration capability of cells remains unclear. Here, by utilizing maskless photolithography with a digital micromirror device (DMD), a microchannel with precisely controlled width and wall stiffness (similar to those exhibited by natural tissues) is fabricated. We find that increasing the rigidity of the confining wall leads to a more reduced nuclear volume but has no detectable influence on the myosin expression level in the cells. More interestingly, a biphasic trend of the cell speed is observed, with the migration velocity reaching its minimum at an intermediate wall rigidity of ∼10 kPa. A motor-clutch-based pulling race model is then proposed, which suggests that such biphasic dependence is due to the fact that a very soft channel wall will result in small deformation of the nucleus and consequently reduced cell-wall friction, while larger myosin-based crawling force can be triggered by a stiff confining boundary, both leading to a relatively high migration speed. These findings could provide critical insights into novel strategies for controlling the movement of cells and the design of high-performance biological materials.