Mechanical behaviors of filopodia protrusion-driven cell fusion

• We showed that the filopodia protrusion force induced significant bending of cell membrane that was essential for membrane fusion between neighboring cells and then eventually induced the formation of multinucleated syncytia. • Molecular dynamics simulations offer a deeper insight into how membrane curvature modulates the fusion efficiency, establishing a new dimension to our understanding of fusion regulation. • There was an optimal cell density for fastest cell fusion. The fusion rate increased with cell density at the moderate cell density, but decreased at high cell densities. Cell fusion is a basic biological process that plays critical roles in both physiological and pathological processes. However, how mechanical factors influence the fusion process is not fully understood. In this study, we reported filopodia-mediated fusion among MCF-7 cells. We showed that the filopodia protrusion force induced significant bending of the cell membrane, which was essential for membrane fusion between neighboring cells, and then eventually induced the formation of multinucleated syncytia. The inhibition of actin polymerization significantly reduced the fusion ratio, whereas increased actin polymerization promoted fusion. We found that several factors influence the fusion process, e.g., the cell density, substrate pattern, and stiffness. For example, cell density has a significant effect on cell fusion. There was an optimal cell density for cell fusion. The fusion probability increased with increasing cell density within a moderate cell density range but decreased within a high cell density range. Substrate properties also influence the fusion behavior. For example, the fusion ratio was reduced on nanogrooved surfaces and soft substrates because the surface pattern restricted cell alignment and motility, and soft substrates reduced the activity of the actin dynamics of filopodia for cell fusion. This study not only contributes to our understanding of the basic biology of cell fusion but also has important implications for understanding the mechanisms of cancer progression and potential therapeutic intervention methods.