Tailoring Cellular Function: The Contribution of the Nucleus in Mechanotransduction

Abstract

Cells sense a variety of different mechanochemical stimuli and promptly react to such signals by reshaping their morphology and adapting their structural organization and tensional state. Cell reactions to mechanical stimuli arising from the local microenvironment, mechanotransduction, play a crucial role in many cellular functions in both physiological and pathological conditions. To decipher this complex process, several studies have been undertaken to develop engineered materials and devices as tools to properly control cell mechanical state and evaluate cellular responses. Recent reports highlight how the nucleus serves as an important mechanosensor organelle and governs cell mechanoresponse. In this review, we will introduce the basic mechanisms linking cytoskeleton organization to the nucleus and how this reacts to mechanical properties of the cell microenvironment. We will also discuss how perturbations of nucleus-cytoskeleton connections, affecting mechanotransduction, influence health and disease. Moreover, we will present some of the main technological tools used to characterize and perturb the nuclear mechanical state.

Keywords: LINC complex; cell nucleus; mechanosensing; mechanotransduction; nuclear envelope.

FIGURE 1

Cartoon representing the nucleus–cytoskeleton–extracellular matrix connections in cells in a low contractility state (i.e., weak adhesions) (A) or in high contractility one (i.e., strong adhesions) (B). On (A), cells poorly adhere to the substrate and develop few and small focal adhesions and thin stress fibers (red lines). Cells in this state are characterized by cytoplasmic localization of YAP and often present nuclear envelope (NE) invaginations. In (B), cells well adhere and spread on the substrate and form more and bigger focal adhesions as well as thick stress fibers. This induces a higher internal tension then transmitted to the NE, leading to nuclear invagination disappearance and nuclear translocation of YAP. NE is here represented as a double bilayer, supported by the Lamin meshwork in the nucleoplasm, and connected to the cytoskeleton by the LINC complex made up of SUN (SUN1/2) and KASH (Nesprins) domain containing enzymes, and Emerin.

FIGURE 2

Methodologies to analyze mechanical features of cell nuclei. The cartoon shows different approaches to measure nuclear mechanical cues. Nuclear stiffness and viscosity can be measured by evaluating stress–strain curves generated by applying controlled mechanical perturbations through suctioning/micropipetting, atomic force microscopy (AFM), active–passive micro/nano-rheology (Brownian Motion/Particle Tracking), nano-pillar mediated nuclear deformation, and optical trap. On the other hand, tension exerted on the nuclear envelope can be quantified employing FRET probes genetically encoded into LINC proteins (Mini-Nesprin-2G), nucleoplasm/inner nuclear membrane translocation of cytoplasmic phospholipase A2 (cPLA2), and FliptR (fluorescent lipid tension reporter) membrane probes.

FIGURE 3

Cartoons showing different strategies to perturb the nuclear tensional state. Mechanical properties of cell nuclei can be altered using different methodologies. Forces can be applied on cells by compression, stretching, and squeezing devices (A–C). Nuclear tensional state can also be indirectly controlled by altering cellular adhesion processes (D–F). Here, chemical patterning (D), topographical patterning (E), and substrate stiffness modulation (F) can be exploited to alter cellular shape causing cytoskeletal component reorganization.