Nanoscale mechanics guides cellular decision making

Abstract

This study used novel, force-limited nanoscale tension gauges to investigate how force and substrate stiffness guide cellular decision-making during initial cell attachment and spreading on deformable substrates. The well-established dependence of cell traction and spreading on substrate stiffness has been attributed to levels of force exerted on molecular components in focal contacts. The molecular tension gauges used in this study enabled direct estimates of threshold, pico Newton forces that instructed decision-making at different stages of cell attachment, spreading, and adhesion maturation. Results show that the force thresholds controlling cellular adhesion and spreading transitions depend on substrate stiffness. Reported findings agree qualitatively with a proposed model that attributes rigidity-dependent differences in cell spreading to stiffness-dependent rates of competing biochemical processes. Moreover, estimated magnitudes of force thresholds governing transitions in cell attachment and spreading, based on these in situ measurements, were in remarkable agreement with prior less direct measurements.

Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity

“…A prior study of epithelial cells reported changes in focal adhesion size and area in cells on both 40kPa and 8.8 kPa hydrogels [26]. However, the present study used softer 1.1 kPa gels, and softer substrates are well known to reduce integrin activation and ligand binding [24,48,53]. But VE-cadherin-mediated force transduction activates phospho-inositide-3-kinase, which can activate integrins by inside-out signaling [26].…”

Substrate Resistance to Traction Forces Controls Fibroblast Polarization

“…For example, if the link between ligand and substrate cannot sustain sufficient force, cells are unable to adhere independent of the stiffness of the underlying substrate (18). Besides this extreme, binary case, a range of potential force-bearing linkages can exist, which have been shown to affect force loading (19)(20)(21). Moreover, traction force-induced changes in conformation of large ECM proteins such as fibronectin (FN) can alter receptor-ligand engagement and dynamics (22).…”

Matrix Nanopatterning Regulates Mesenchymal Differentiation through Focal Adhesion Size and Distribution According to Cell Fate

“…Integrin-mediated mechanotransduction occurs via the linkage between integrins binding their ECM ligands and the cytoskeleton through a ~40 nm-high focal adhesion (FA) core [6]. Interaction between ECM–FAs operate at the nanoscale: a nano-mechanical coupling exists between matrix characteristics and integrin-mediated cell adhesion, guiding cell behavior [7]. Therefore, nanopatterned surfaces have been extensively used to study ECM–cell interactions at the nanoscale and to identify the geometric cues that initiate and guide cell adhesion, such as spatial sensing [8], which in turn conditions cell spreading [9], migration [10], and differentiation [11].…”