How do the cells sense and respond to the microenvironment mechanics?

In recent years, there is an increasing interest in understanding the mechanical interactions between cells and their microenvironment. The cellular mechanical sensing and response have been clearly proven to play a decisive role in cell behaviors including adhesion, migration, proliferation, differentiation, etc., as well as embryonic development, tissue growth, and pathological process in life sciences. Therefore, the physical properties such as stiffness, morphology, ligand distribution, etc., have become the attractive factors for the design of novel biomaterials. However, how these static physical parameters mechanical stimulate the cells and how the cells sense the mechanical properties of the microenvironment are interesting but challenging questions. Herein, we introduce the mechanism of cell mechanical sensing and response in detail. The key role of the intracellular force in these processes is highlighted, while the force transmission and transduction are explained in the molecular level. It will help to understand the interactions between cells and biomaterials, which promotes the studies in the fields of cell mechanobiology as well as the development of new biomaterials. The adhesive proteins, including integrins and cadherins, on the cell membrane bind to and are activated by the ligands in the microenvironment. The intracellular domain of the adhesive proteins connects to the actin filaments through structural proteins. The activated myosin subsequently binds to the actin filaments and generates traction force, which is transmitted back to the microenvironment along the molecular clutch (the physically linked protein chain including adhesive proteins, structural proteins, cytoskeletal proteins, etc.). The microenvironment generates reaction force to balance the intracellular traction. Higher microenvironment stiffness can offer larger reaction force, resulting in the continuous increase of intracellular traction force. When the traction force is above a threshold, the structural protein talin, linked within the molecular clutch, is unfolded by force. The unfolded/activated talin further causes the conformation change of vinculin, paxillin, and focal adhesion kinase (FAK) under force. These activated proteins recruit adhesive proteins and cross-link single molecular clutches to concentrate the traction force. Meanwhile, the newly exposed active sites of these proteins activate the enzymes to transduce the mechanical cues to biochemical factors, which further catalyze the activation of the actomyosin to generate more traction force as well as activate the transcription factors and transcriptional regulators. At the same time, the other end of the actomyosin cytoskeleton links to and stretch the nucleoskeleton Lamin A/C through the LINC complex in nuclear membrane. The lamin A/C proteins assemble into intermediate filaments, which further stretch and unfold the condensed chromatin. The force on the molecular clutch also open the pores of the nuclear membrane. Thus, the activated transcription factors and transcriptional regulators can enter the nucleus and target to the unfolded chromatin. As the results, new proteins are expressed and the phenotype of cells is changed. This process, cells recognize the mechanical cues of their microenvironment and transduce the mechanical stimuli to biochemical signals, is called mechanotransduction. The studies of cell mechanosensing and mechanoresponse not only offer the guidance for designing the mechanical properties of the new biomaterials, but also offer new weapons to regulate cell behaviors and functions, which can promote the development of tissue engineering, regenerative medicine, as well as disease therapeutics.