Ultrasensitivity of Cell Adhesion to the Differential Mechanical Cues and Requirement of Reversibility

Abstract

Cell adhesion regulates critical cellular functions in adherent cells. Yet, the fundamental mechanism during the early events in cell adhesion remains unclear. At the most elementary level, the sensing of the mechanical environment must be performed by single molecules in mechanical contact with the environment, and the cell then must be able to process the single molecular events for its decision making. Herein, we utilized our recently developed DNA tether called tension gauge tether (TGT) to study the mechanical requirements of integrin-mediated cell adhesion. Previously, we showed that cells need to experience a threshold force of 40 pN through single integrin-ligand bonds to initiate adhesion and spreading and that just a few copies of strong (∼ 54 pN) TGTs per cell are enough elicit to cell adhesion and spreading as long as there is a high density of weak tethers. Here, we show that 23 pN and 12 pN tethers, which are unable to induce cell adhesion individually, can induce cell adhesion if they are presented together to the cell. Therefore, the cells appear to be able to perform differential force measurements instead of absolute force measurements. Furthermore, we show, by direct single molecule imaging, a cell needs only two copies of 23 pN tethers for such differential force measurements. We also show that such ultrasensitivity to differential mechanical cues requires reversible formation of the weak mechanical tugs through integrins, suggesting that the presence of relatively stronger tethers as nuclei may keep the cell membrane close to the surface. How the cells can make an important decision of adhesion and spreading in response to the presence of just two integrins that experience stronger tension than other integrin molecules do without amplifying noise is current investigation.