Mechanically-Induced Remodeling of Cell Surfaces: A Pathway for Tunneling Nanotube-like Protrusions

The cell surface is a dynamic interface where mechanical cues are converted into biochemical signals. Its structure and function rely on the interplay between the plasma membrane and the underlying actomyosin cortex, which governs key processes such as migration, shape changes, and mechanosensing [1]. Yet critical questions remain: What happens when a localized, sustained point force is applied for several minutes? Can it reshape the cell surface, triggering the formation of a new protrusion? We address these questions by combining optical tweezers (OT)-based tether extraction with high-resolution live-cell imaging. Our results reveals that when the applied force is abruptly stopped after tether formation, the cell surface undergoes rapid recoil. Conversely, a sustained application of force for five minutes results in stiffening and delayed recoil, a phenomenon captured by a phenomenological model that describes this time-dependent adaptation. This model links tether stiffening to increased damping, which is associated with the progressive recruitment of F-actin into tethers and changes in their force profiles, transitioning from steady-state plateaus to force spikes.

The study demonstrates that this mechanosensitive behavior is universal across various cell types and relies on the integrity of the membrane and actomyosin cytoskeleton. It occurs through a formin-driven process, independent of Arp2/3. The generated tubes appeared fully integrated to cell surfaces, were able to nucleate newly cell surface protrusions, and exhibited dynamic movement and when a tether was anchored to a neighboring cell, it formed a stable, F-actin-rich bridge that enabled vesicle-like transfer, mimicking TNT-like protrusions. These results reveal that cells dynamically remodel their surface in response to persistent point forces, leading to the formation of tunneling nanotube (TNT)-like protrusions. Such refined mechanical control, could enable unprecedented manipulation of cells, with far-reaching consequences for intercellular signaling and even disease progression.