Mechanotransduction model provides insights into integrin clustering/disassembly dynamics and associated FAK phosphorylation.

Cellular behaviors such as migration, spreading, and differentiation arise from the interplay of cell–matrix interactions. The comprehension of this interplay has been advanced by the motor-clutch model, a theoretical framework that captures the binding-unbinding kinetics of mechanosensitive membrane-bound proteins involved in mechanochemical signaling, such as integrins. Since its introduction and subsequent development as a computational tool, the motor clutch model has been instrumental in elucidating the impact of biophysical factors on cellular mechanobiology. This review aims to provide a comprehensive overview of recent advances in the motor-clutch modeling framework, its role in elucidating the relationships between mechanical forces and cellular processes, and its potential applications in mechanomedicine.

Positive autoregulation (PAR), one type of network motifs, provides a high phenotypic heterogeneity for cells to better adapt to their microenvironments. Typical mechanosensitive proteins can also form PAR, e.g., integrin mediated PAR, but the role of such mechanical PAR in physiological development and pathological process remains elusive. In this study, we found that transforming growth factor β1 (TGF-β1) and integrin levels decrease with tissue softening after the development of paradentium in vivo in rat model of periodontitis (an inflammatory disease with bone defect). Interestingly, TGF-β1 could induce the formation of mechanical PAR involving the integrin-FAK-YAP axis in mesenchymal stem cells (MSCs) by both in vitro experiments and in silico computational model. The computational model predicted a mechanical PAR involving the bimodal distribution of focus adhesions, which enables cells to accurately perceive extracellular mechanical cues. Thus, our analysis of TGF-β1 mediated mechanosensing mechanism on MSCs may help to better understand the molecular process underlying bone regeneration.

Durotaxis – the ability of cells to sense and migrate along stiffness gradients – is important for embryonic development and has been implicated in pathologies including fibrosis and cancer. Although cellular processes can sometimes turn toward softer environments, durotaxis at the level of cells has thus far been observed exclusively as migration from soft to stiff regions. The molecular basis of durotaxis, especially the factors that contribute to different durotactic behaviors in various cell types, are still inadequately understood. With the recent discovery of ‘optimal stiffness’, where cells generate maximal traction forces on substrates in an intermediate stiffness range, we hypothesized that some migratory cells may be capable of moving away from stiff environments and toward matrix on which they can generate more traction. Combining hydrogel-based stiffness gradients, live-cell imaging, genetic manipulations, and computational modeling, we found that cells move preferentially toward their stiffness optimum for maximal force transmission. Importantly, we directly observed biased migration toward softer environments, i.e. ‘negative durotaxis’, in human glioblastoma cells. This directional migration did not coincide with changes in FAK, ERK or YAP signaling, or with altered actomyosin contractility. Instead, integrin-mediated adhesion and motor-clutch dynamics alone are sufficient to generate asymmetric traction to drive both positive and negative durotaxis. We verified this mechanistically by applying a motor-clutch-based model to explain negative durotaxis in the glioblastoma cells and in neurites, and experimentally by switching breast cancer cells from positive to negative durotaxis via talin downregulation. Our results identify the likely molecular mechanisms of durotaxis, with a cell’s contractile and adhesive machinery dictating its capacity to exert traction on mechanically distinct substrates, directing cell migration.