Matrix stiffness reverses the effect of actomyosin tension on cell proliferation

Abstract

SummaryThe stiffness of the extracellular matrix exerts powerful effects on cell proliferation and differentiation, but the mechanisms transducing matrix stiffness into cellular fate decisions remain poorly understood. Two widely reported responses to matrix stiffening are increases in actomyosin contractility and cell proliferation. To delineate their relationship, we modulated cytoskeletal tension in cells grown across a physiological range of matrix stiffnesses. On both synthetic and naturally derived soft matrices, and across a panel of cell types, we observed a striking reversal of the effect of inhibiting actomyosin contractility, switching from the attenuation of proliferation on rigid substrates to the robust promotion of proliferation on soft matrices. Inhibiting contractility on soft matrices decoupled proliferation from cytoskeletal tension and focal adhesion organization, but not from cell spread area. Our results demonstrate that matrix stiffness and actomyosin contractility converge on cell spreading in an unexpected fashion to control a key aspect of cell fate.

Contractility of single cardiomyocytes differentiated from pluripotent stem cells depends on physiological shape and substrate stiffness

“…Generally, tension along the cell membrane increases with the aspect ratio of adherent cells (26). Intracellular tension also increases with substrate stiffness (27,28), and the contractility of primary neonatal murine CMs varies with substrate stiffness (18,29).…”

“…Mechanical output was highest on hydrogels with the stiffness of healthy myocardium (6 and 10 kPa). However, intracellular tension also decreases with decreasing substrate stiffness (27), and fewer engineered hPSC-CMs on 6-kPa hydrogels retained their myofibril organization over the contractile cycle but instead exhibited myofibril buckling during relaxation (SI Appendix, Fig. S9 and Movies S5-S8).…”

Cellular Morphology-Mediated Proliferation and Drug Sensitivity of Breast Cancer Cells

“…The extensive studies have been made in a mechanotransduction via surface topography and stiffness on the substrates, in which the cells respond to applied forces and exert forces in the substrate (ECM) [24][25][26]. Such forces can change cell morphology and cytoskeletal structure due to the traction forces (contractility) generation, which influence cell response and cell fate.…”

“…Such forces can change cell morphology and cytoskeletal structure due to the traction forces (contractility) generation, which influence cell response and cell fate. Apart from this, nuclear factor kappa-B (NF-κB) activation is associated with the spreading parameter of (Nuclear/Cytoplasm) [26]. NF-κB is known to be involved in the inflammatory and tumor development including cellular proliferation, apoptosis and drug sensitivity [8,[25][26][27][28][29].…”

“…Apart from this, nuclear factor kappa-B (NF-κB) activation is associated with the spreading parameter of (Nuclear/Cytoplasm) [26]. NF-κB is known to be involved in the inflammatory and tumor development including cellular proliferation, apoptosis and drug sensitivity [8,[25][26][27][28][29]. Additionally several groups reported NF-κB was regulated by actomyosin contractility [27,30,31].…”