The importance of dynamic cell-cell adhesions in the sorting-out in multicellular structures

Cell-cell adhesions are a fundamental driver of cellular organization in tissues. While prevailing models emphasize adhesion strength and assume rapid turnover, the role of adhesion dynamics is overlooked. Here, we show that the kinetics of adhesion formation and dissociation are decisive regulators of multicellular organization. Using optogenetically-controlled cell surface molecules, we reversibly induce cell-cell adhesions and tune their on/off kinetics via pulsed illumination. In spheroid cultures, continuously enforced cell-cell adhesions lock cells in place, producing kinetically trapped structures that prevent cell rearrangement, compaction and sorting. By contrast, dynamically exchanging cell-cell adhesions allow cells to reposition to maximize adhesion to neighbours, increase cell-cell contact areas, and yield compact spheroids with predictable sorting patterns. Thus, adhesion dynamics constitute an independent control axis for compaction and sorting-out, enabling optical programming of 3D microtissues for bottom-up tissue engineering.