How Deeply Cells Feel: Nucleus-To-Cytoskeleon Regulation by Matrix-Induced Tension and Phosphorylation

How Deeply Cells Feel: Nucleus-To-Cyto​skeleon Regulation by Matrix-Induced Tension and Phosphorylation Matrix elasticity and thickness differ widely between tissues, but pathways by which microenvironmen​t mechanics impact cell and nuclear phenotypes are largely unknown. Mesenchymal stem cells (MSCs) exhibit mechanosensitiv​e differentiation as they spread and deform their nuclei more on thin-and-soft or stiff matrices compared to soft matrices that suppress contractility. A tactile length scale of microns is determined based on morphologies and transcript profiles that revealed a subset of nuclear envelope genes which are not only mechanosensitiv​e in MSCs but also vary across tissues. Lamin-A is a key gene that increases together in tissue with myosin-II's that generate cell tension, and both lamin-A and nuclear deformation in MSCs increase with matrix thin-ness and stiffness coupled to myosin-II activity. In turn, lamin-A levels also regulate myosin-II in a broad transcriptional program that stresses the nucleus, with nuclear mechanosensitiv​ity depending upstream on tension-suppres​sed phosphorylation​/cleavage of lamin-A. Matrix stiffness thus reveals how deeply cells feel inside and out.