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From the Department of Medicine, Gastroenterology Division, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Superficial injury involving the mucosa of the gastrointestinal
tract heals by a process termed restitution that involves epithelial
sheet movement into the damaged area. The forces that drive epithelial
sheet movement are only partially understood, although it is
known to involve changes in the morphology of cells bordering the
damage, such as the formation of large, flat,
cytoplasmic extensions termed lamellae. We investigated the mechanism
of epithelial sheet movement by following the response of the actin
cytoskeleton and specific integrins (
6ß4,
6ß1, and 3ß1) to wounding. To model this event
in vitro, monolayers of T84 cells,
well-differentiated colon carcinoma cells, were damaged by
aspiration and the ensuing response was analyzed by a combination of
time-lapse video microscopy, fluorescence confocal microscopy
and antibody inhibition assays. We show that wound healing begins with
retraction of the monolayer. 6ß4 integrin is localized on the
basal surface in structures referred to as type II hemidesmosomes that
persist throughout this early stage. We hypothesize that these
structures adhere to the substrate and function to retard retraction.
Once retraction ceases, the wound is contracted initially by
actin purse strings and then lamellae. Purse strings and lamellae
produce a pulling force on surrounding cells, inducing them to
flatten into the wound. In the case of lamellae, we detected
actin suspension cables that appear to transduce this pulling force. As
marginal cells produce lamellae, their basal type II
hemidesmosomes disappear and the 6 integrins appear evenly
distributed over lamellae surfaces. Antibodies directed against the
6 subunit inhibit lamellae formation, indicating that
redistribution of the 6 integrins may contribute to the protrusion
of these structures. Antibodies directed against the 3ß1 integrin
also reduce the size and number of lamellae. This integrin’s
contribution to lamellae extension is most likely related to its
localization at the leading edge of emerging protrusions. In
summary, wounds in epithelial sheets initially retract,
and then are contracted by first an actin purse string and then
lamellae, both of which serve to pull the surrounding cells
into the denuded area. The 6 integrins, particularly
6ß4, help contain retraction and both the 6 integrins
and 3ß1 integrin contribute to lamellae formation.
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