Fig. 5: Quantitative model reproduces the experimentally observed impact of fast cyclic change in substrate rigidity.

a Schematic of the molecular clutch model of a cell attached to a substrate. b–d Average migration distance, MSD and FA area of hMSCs on substrates with different mechanical properties over 12 h in the experiments and simulations. In b-d, n = 204, 224 and 214 (1 min cycle, 10 min cycle, and 2.2 kPa) cells were examined, each from 3 independent experiments. In d, *** = p < 0.01, unpaired, two-tailed t-test. (e-f) Average migration distance and MSD of hMSCs on substrates with fast cyclic rigidity changes over 12 h, slowing the actin polymerization rate (–Rac) and lowering the number of motors (–pMyosin) in the experiments and simulations. In e, f, n = 204, 200 and 222 (Ctrl, –Rac, and –pMyosin) cells were examined, each from 3 independent experiments. In b, c, e, and f, the experimental data are presented as mean values (points) +/- standard deviation (shaded region); the simulation results are shown as mean values (solid line). g Bond lifetime (time elapsed between initial attachment of a single bond to its breakage) versus interval of cyclic change. Data are presented as mean values +/- standard deviation (error bars), which reflects the predicted variability. h Fast cyclic substrate rigidity changes trigger rapid cell migration. I) → II) Fast cyclic substrate rigidity changes periodically accumulate signalling proteins because the slow dephosphorylation rate of pFAK during the softening phase and the rapid phosphorylation rate during the rigidifying phase. The accumulated signalling proteins further catalyse the mechanotransduction pathways to promote actin polymerization, resulting in cell elongation. II) → III) The continuous accumulation of mechanosignalling protein pMyosin IIa makes the pMyosin IIa-generated intracellular force continue to exceed the adhesion force between cell and ECM. As a result, the entire focal adhesion on one side of the cell collapses and the cell snap-backs to the other side, which leads to rapid cell migration. In all panels, the simulation results are calculated from 200 independent simulation runs. Source data are provided as a Source Data file.