Biology subjects

Kechagia, Z.

Publications and source records attributed to Kechagia, Z..

3 recordsLinked to original sources

bioRxiv2024

Cell-matrix force transmission regulates the loss of naïve pluripotency in mouse embryonic stem cells.

The first step in the differentiation of mouse embryonic stem cells (mESCs) is the loss of naive pluripotency. This step involves a major reshaping of cells from a rounded to a spread, adhesive phenotype. Whereas such reshaping is typically associated with increased force transmission to the extracellular matrix (ECM), the magnitude and role of cell-matrix forces in the loss of naive pluripotency is unknown. Here, we show that cell-matrix forces increase during, and are required for, the loss of naive pluripotency in mESCs. Using traction force microscopy, we show that mESCs progressively increase cell-traction forces and mechanotransduction markers as naive pluripotency dissolves. Modulation of force transmission through myosin inhibition, substrate stiffness, or spatial differences within mESC colonies regulates the process. Increased force is triggered by GSK3-mediated signalling, and the effect of force is regulated in part by its transmission to the cell nucleus. Our work unveils a major role of cell-ECM forces in pluripotency dissolution, adding an important aspect to the interplay between biochemical and biophysical cues that drive this process.

developmental biology↗

bioRxiv2022

The laminin-keratin link shields the nucleus from mechanical deformation and signalling

The mechanical properties of the extracellular matrix (ECM) dictate tissue behaviour. In epithelial tissues, laminin is both a very abundant ECM component, and a key supporting element. Here we show that laminin hinders the mechanoresponses of breast epithelial cells by shielding the nucleus from mechanical deformation. Coating substrates with laminin-111, unlike fibronectin or collagen I, impairs cell response to substrate rigidity, and YAP nuclear localization. Blocking the laminin-specific integrin {beta}4 increases nuclear YAP ratios in a rigidity dependent manner, without affecting cell forces or focal adhesions. By combining mechanical perturbations and mathematical modelling, we show that {beta}4 integrins establish a mechanical linkage between the substrate and the keratin cytoskeleton, which stiffens the network and shields the nucleus from actomyosin-mediated mechanical deformation. In turn, this affects nuclear YAP mechanoresponses and chromatin methylation. Our results demonstrate a mechanism by which tissues can regulate their sensitivity to mechanical signals.

cell biology↗

bioRxiv2021

The force loading rate drives cell mechanosensing through both reinforcement and fluidization

Cell response to force regulates essential processes in health and disease. However, the fundamental mechanical variables that cells sense and respond to remain unclear. Here we show that the rate of force application (loading rate) drives mechanosensing, as predicted by a molecular clutch model. By applying dynamic force regimes to cells through substrate stretching, optical tweezers, and atomic force microscopy, we find that increasing loading rates trigger talin-dependent mechanosensing, leading to adhesion growth and reinforcement, and YAP nuclear localization. However, above a given threshold the actin cytoskeleton undergoes fluidization and softens, decreasing loading rates and preventing reinforcement. By stretching rat lungs in vivo, we show that a similar phenomenon occurs at the organ level. Our results show that cell sensing of external forces and of passive mechanical parameters (like tissue stiffness) can be understood through the same mechanisms, driven by the properties under force of the mechanosensing molecules involved.

biophysics↗