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bioRxiv · 10.64898/2026.03.23.713577

Transient contractility attenuation reprograms epithelial cells into a protrusion-driven state that drives tissue fluidization

WP, S.·Liu, S.·Nguyen, T. P.·Mishra, P. K.·Pratiman, D.·Gupta, A. S.·Hirashima, T.
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Abstract

Collective cell migration drives tissue morphogenesis, repair and remodeling, and is often accompanied by transitions from solid-like to fluid-like states. While such tissue fluidization has been linked to physical parameters such as cell density, shape and activity, how it is actively regulated by mechano-chemical interplay remains unclear. Previous research has shown that transient attenuation of actomyosin contractility induces a transition from pulsatile, spatially confined motion to coherent, persistent long-range collective flow; however, the underlying cellular and signaling mechanisms remain unclear. Here we uncover the mechanistic basis by which transient perturbation of cell contractility reprograms the migration mode of confluent epithelial cells into a protrusion-driven, fluidizing state, by combining kinase-reporter live imaging, force measurements and mathematical modeling. This transition arises from coordinated changes in cell morphology and mechanics, including reduced cortical tension and greater stretch-induced cell strain, together with enhanced cell-substrate adhesion and force transmission. At the signaling level, this process is accompanied by a rewiring of extracellular signal-regulated kinase (ERK)-mediated mechanotransduction toward a protrusion-coupled mode that sustains migration even under fully confluent conditions. Consistently, a multicellular computational model further demonstrates that protrusion-driven migration is sufficient to promote shape-velocity alignment and drive a transition from caged to flocking-like collective states. Together, our results identify transient contractility attenuation followed by recovery as a trigger for a protrusion-driven state that fluidizes confluent epithelial tissues through coordinated remodeling of cytoskeletal, adhesive, and signaling systems.

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WP, S., Liu, S., Nguyen, T. P., Mishra, P. K., Pratiman, D., Gupta, A. S., Hirashima, T.. 2026-03-25. Transient contractility attenuation reprograms epithelial cells into a protrusion-driven state that drives tissue fluidization. https://doi.org/10.64898/2026.03.23.713577

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