Cellular mechanosensitivity to substrate stiffness decreases with increasing dissimilarity to cell stiffness

Computational modelling has received increasing attention to investigate multi-scale coupled problems in micro-heterogeneous biological structures such as cells. In the current study, we investigated for a single cell the effects of (1) different cell-substrate attachment (2) and different substrate modulus [Formula: see text] on intracellular deformations. A fibroblast was geometrically reconstructed from confocal micrographs. Finite element models of the cell on a planar substrate were developed. Intracellular deformations due to substrate stretch of [Formula: see text], were assessed for: (1) cell-substrate attachment implemented as full basal contact (FC) and 124 focal adhesions (FA), respectively, and [Formula: see text]140 KPa and (2) [Formula: see text], 140, 1000, and 10,000 KPa, respectively, and FA attachment. The largest strains in cytosol, nucleus and cell membrane were higher for FC (1.35[Formula: see text], 0.235[Formula: see text] and 0.6[Formula: see text]) than for FA attachment (0.0952[Formula: see text], 0.0472[Formula: see text] and 0.05[Formula: see text]). For increasing [Formula: see text], the largest maximum principal strain was 4.4[Formula: see text], 5[Formula: see text], 5.3[Formula: see text] and 5.3[Formula: see text] in the membrane, 9.5[Formula: see text], 1.1[Formula: see text], 1.2[Formula: see text] and 1.2[Formula: see text] in the cytosol, and 4.5[Formula: see text], 5.3[Formula: see text], 5.7[Formula: see text] and 5.7[Formula: see text] in the nucleus. The results show (1) the importance of representing FA in cell models and (2) higher cellular mechanical sensitivity for substrate stiffness changes in the range of cell stiffness. The latter indicates that matching substrate stiffness to cell stiffness, and moderate variation of the former is very effective for controlled variation of cell deformation. The developed methodology is useful for parametric studies on cellular mechanics to obtain quantitative data of subcellular strains and stresses that cannot easily be measured experimentally.