부산대학교 도서관

Cells interact with the extracellular matrix (ECM) via cell–ECM adhesions. These physical interactions are transduced into biochemical signals inside the cell which influence cell behaviour. Although cell–ECM interactions have been studied extensively, it is not completely understood how immature (nascent) adhesions develop into mature (focal) adhesions and how mechanical forces influence this process. Given the small size, dynamic nature and short lifetimes of nascent adhesions, studying them using conventional microscopic and experimental techniques is challenging. Computational modelling provides a valuable resource for simulating and exploring various "what if?" scenarios in silico and identifying key molecular components and mechanisms for further investigation. Here, we present a simplified mechano-chemical model based on ordinary differential equations with three major proteins involved in adhesions: integrins, talin and vinculin. Additionally, we incorporate a hypothetical signal molecule that influences adhesion (dis)assembly rates. We find that assembly and disassembly rates need to vary dynamically to limit maturation of nascent adhesions. The model predicts biphasic variation of actin retrograde velocity and maturation fraction with substrate stiffness, with maturation fractions between 18–35%, optimal stiffness of ∼1 pN/nm, and a mechanosensitive range of 1-100 pN/nm, all corresponding to key experimental findings. Sensitivity analyses show robustness of outcomes to small changes in parameter values, allowing model tuning to reflect specific cell types and signaling cascades. The model proposes that signal-dependent disassembly rate variations play an underappreciated role in maturation fraction regulation, which should be investigated further. We also provide predictions on the changes in traction force generation under increased/decreased vinculin concentrations, complementing previous vinculin overexpression/knockout experiments in different cell types. In summary, this work proposes a model framework to robustly simulate the mechanochemical processes underlying adhesion maturation and maintenance, thereby enhancing our fundamental knowledge of cell–ECM interactions. Author summary: The immediate environment of a cell is vastly different in healthy and diseased tissue and influences numerous intracellular processes. Mechanical and chemical properties of the extracellular matrix (ECM) impact cellular processes through various pathways, enabling cells to 'sense' their environment and respond accordingly. Cell-ECM interactions occur through adhesions and are mediated by transmembrane proteins called integrins, which, depending on the ECM properties, can recruit, directly or indirectly, >200 proteins and transduce external signals to intracellular chemical signals. However, how adhesions assemble, grow, and disassemble is poorly understood. Here, using a differential equation-based mechano-chemical computational model, we investigate how substrate stiffness influences adhesion formation, maturation and disassembly. We explicitly include the role of talin and vinculin-based reinforcement in these processes. The model we present is robust and can be fine-tuned for particular cell-types and signalling mechanisms. The simulations predict the highest amount of maturation on substrates of an intermediate, 'optimum' stiffness, and that (dis)assembly rates need to change dynamically for cells to establish this 'optimum'. In summary, our results highlight the importance of vinculin availability in adhesion maturation and reinforcement and aid our understanding of cell adhesion formation and mechanotransduction. [ABSTRACT FROM AUTHOR]