Epithelial self-healing is recapitulated by a 3D biomimetic E-cadherin junction

Significance Injured tissues can self-heal. The healing process requires that tissue first migrate into the injury site and, upon collision with other expanding tissue fronts, switch from migration to cell–cell adhesion to seal the injury mechanically. The minimum signal inducing this switch is unknown due to the complexity of natural healing interfaces. We made a 3D barrier that mimicked the edge of a tissue and induced healing tissues to collide with it. When we coated the barrier with E-cadherin, a key cell–cell adhesion protein, epithelial tissues behaved as if the barrier were a tissue and stably healed against the barrier. This work reveals a key role for E-cadherin in self-healing, and an alternate way to integrate objects into tissue. Epithelial monolayers undergo self-healing when wounded. During healing, cells collectively migrate into the wound site, and the converging tissue fronts collide and form a stable interface. To heal, migrating tissues must form cell–cell adhesions and reorganize from the front-rear polarity characteristic of cell migration to the apical-basal polarity of an epithelium. However, identifying the "stop signal" that induces colliding tissues to cease migrating and heal remains an open question. Epithelial cells form integrin-based adhesions to the basal extracellular matrix (ECM) and E-cadherin–mediated cell–cell adhesions on the orthogonal, lateral surfaces between cells. Current biological tools have been unable to probe this multicellular 3D interface to determine the stop signal. We addressed this problem by developing a unique biointerface that mimicked the 3D organization of epithelial cell adhesions. This "minimal tissue mimic" (MTM) comprised a basal ECM substrate and a vertical surface coated with purified extracellular domain of E-cadherin, and was designed for collision with the healing edge of an epithelial monolayer. Three-dimensional imaging showed that adhesions formed between cells, and the E-cadherin-coated MTM resembled the morphology and dynamics of native epithelial cell–cell junctions and induced the same polarity transition that occurs during epithelial self-healing. These results indicate that E-cadherin presented in the proper 3D context constitutes a minimum essential stop signal to induce self-healing. That the Ecad:Fc MTM stably integrated into an epithelial tissue and reduced migration at the interface suggests that this biointerface is a complimentary approach to existing tissue–material interfaces.

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