Differential cellular contractility as a mechanism for stiffness sensing

TL;DR

This paper proposes a novel mechanism where non-uniform cellular contractility generates localized internal stretch, enabling cells to sense substrate stiffness through stretch-activation of mechanotransductive molecules, independent of focal adhesions.

Contribution

It introduces a contractility-driven model linking substrate stiffness to internal cellular stretch, advancing understanding of cellular mechanosensing mechanisms.

Findings

Localized internal stretch occurs on stiffer substrates.

Stretch-activation of mechanotransductive molecules is independent of focal adhesions.

Cell shape influences the stiffness threshold for mechanotransduction.

Abstract

The ability of cells to sense and respond to the mechanical properties of their environments is fundamental to a range of cellular behaviours, with substrate stiffness increasingly being found to be a key signalling factor. Although active contractility of the cytoskeleton is clearly necessary for stiffness sensing in cells, the physical mechanisms connecting contractility with mechanosensing and molecular conformational change are not well understood. Here we present a contractility-driven mechanism for linking changes in substrate stiffness with internal conformational changes. Cellular contractility is often assumed to imply an associated compressive strain. We show, however, that where the contractility is non-uniform, localized areas of internal stretch can be generated as stiffer substrates are encountered. This suggests a physical mechanism for the stretch-activation of mechanotransductive molecules on stiffer substrates. Importantly, the areas of internal stretch are not co-localized with those traditionally associated with stiffness sensing, e.g. focal adhesions, supporting recent experimental results on whole-cell mechanically-driven mechanotransduction. Considering cellular shape we show that aspect ratio acts as an additional control parameter, so that the onset of positive strain moves to higher stiffness values in elliptical cells.