PIEZO1 regulates leader cell formation and cellular coordination during collective cell migration: An integrative multiscale modeling and experimental study

The collective migration of keratinocytes during wound healing requires both the generation and transmission of mechanical forces for individual cellular locomotion as well as for the coordination of movement across cells. Leader cells initiated along the wound edge transmit mechanical and biochemical cues to ensuing follower cells, ensuring their uniform polarization and coordinated direction of migration, or directionality. Despite the observed importance of mechanical cues in leader cell formation and governing directionality, the underlying biophysical mechanisms remain elusive. The mechanically activated ion channel PIEZO1 was recently identified to play an inhibitory role during the reepithelialization of wounds through retraction of keratinocytes located along the wound edge. Here, through an integrative experimental and mathematical modeling approach, we elucidate PIEZO1's contributions to collective migration. Time-lapse microscopy reveals that PIEZO1 activity inhibits leader cell formation along the wound edge. To probe the relationship between PIEZO1 activity, leader cell formation and inhibition of reepithelialization, we developed an integrative 2D-multiscale model of wound closure that links observations at the single cell and collective cell migration scales. Through numerical simulations and subsequent experimental validation, we found that directionality plays a key role during wound closure and is inhibited by PIEZO1 activity. We propose that PIEZO1-mediated retraction suppresses leader cell formation which inhibits the coordination of directionality between cells during collective migration.