Wounding Induces Motility in Sheets of Corneal Epithelial Cells through Loss of Spatial Constraints

Block, Ethan R.; Matela, Abigail R.; SundarRaj, Nirmala; Iszkula, Erik R.; Klarlund, Jes K.

doi:10.1074/jbc.m401058200

Cited by 125 publications

(161 citation statements)

References 47 publications

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“…These observations are compatible with those dealing with corneal epithelia (11) or endothelial cells (12) in the sense that a true injury of the border cells is not necessary to trigger the migration of these cells. This conclusion validates the underlying assumption of many studies dealing with in vitro wound healing.…”

Section: Migration Triggered By a Model Wound And Advantages Of The Asupporting

confidence: 77%

Collective migration of an epithelial monolayer in response to a model wound

Poujade

Grasland-Mongrain

Hertzog

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

852

997

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Using an original microfabrication-based technique, we experimentally study situations in which a virgin surface is presented to a confluent epithelium with no damage made to the cells. Although inspired by wound-healing experiments, the situation is markedly different from classical scratch wounding because it focuses on the influence of the free surface and uncouples it from the other possible contributions such as cell damage and/or permeabilization. Dealing with Madin-Darby canine kidney cells on various surfaces, we found that a sudden release of the available surface is sufficient to trigger collective motility. This migration is independent of the proliferation of the cells that mainly takes place on the fraction of the surface initially covered. We find that this motility is characterized by a duality between collective and individual behaviors. On the one hand, the velocity fields within the monolayer are very long range and involve many cells in a coordinated way. On the other hand, we have identified very active ''leader cells'' that precede a small cohort and destabilize the border by a fingering instability. The sides of the fingers reveal a pluricellular actin ''belt'' that may be at the origin of a mechanical signaling between the leader and the followers. Experiments performed with autocrine cells constitutively expressing hepatocyte growth factor (HGF) or in the presence of exogenous HGF show a higher average velocity of the border and no leader.collective motility ͉ epithelial cells ͉ microfabrication ͉ wound healing

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Section: Migration Triggered By a Model Wound And Advantages Of The Asupporting

confidence: 77%

Collective migration of an epithelial monolayer in response to a model wound

Poujade

Grasland-Mongrain

Hertzog

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

852

997

View full text Add to dashboard Cite

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“…HB-EGF release has been detected in a number of systems including acute renal injury and wounded keratinocytes (Sakai et al, 1997;Tokumaru et al 2000). The use of functional blocking antibodies inhibited the responses induced by this release (Shah et al 2004, Block et al 2004, Xu et al 2004. In our system HB-EGF blocking antibody inhibited wound induced EGFR phosphorylation ( Figure 3).…”

Section: Discussionmentioning

confidence: 64%

“…A number of investigators have shown that stimulation of GPCRs leads to release of HB-EGF and activation of the EGFR (Block et al, 2004;Pierce et al, 2001;Prenzel et al, 1999;Schafer et al 2004b;Shah et al 2004). Activation of the GPCRs can stimulate the ADAM family of matrix metalloproteases that release the EGFR ligands (Fischer et al, 2004;Yan et al, 2002;Schafer et al, 2004b).…”

Section: Discussionmentioning

confidence: 99%

Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway

Boucher

Yang

Mayo

et al. 2007

Experimental Eye Research

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The early events that occur rapidly after injury trigger signal cascades that are essential for proper wound closure of corneal epithelial cells. We hypothesize that injury releases ATP, which stimulates purinergic receptors and elicits the phosphorylation of epidermal growth factor receptor (EGFR) tyrosine residues and subsequent cell migration by a MMP and HB-EGF dependent pathway. We demonstrated that the inhibition of purinergic receptors with the antagonist, Reactive Blue 2, abrogated the phosphorylation of EGFR and ERK. Preincubation of cells with the EGFR kinase inhibitor, AG1478, and subsequent stimulation by injury or ATP resulted in a decrease in phosphorylation of EGFR and migration. Furthermore, downregulation of EGFR by siRNA, inhibited the EGF induced intracellular Ca 2+ wave. However, the response to injury and ATP was retained indicating the presence of 2 signaling pathways. Inhibition with either CRM197 or TIMP-3 decreased injury and nucleotide induced phosphorylation of both EGFR and ERK. Incubation in the presence of a functional blocking antibody to HB-EGF also resulted in a decrease in the phosphorylation of EGFR. In addition, cell migration was inhibited by CRM197 and rescued when cells were incubated with HB-EGF. We showed that injury induced phosphorylation of specific tyrosine residues and found that a similar pattern of phosphorylation was induced by trinucleotides. These studies indicate that injury induced purinergic receptor activation leads to phosphorylation of EGFR, ERK and migration.

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“…A particularly intriguing study on mammalian cells has shown that the activation of EGFR occurs upon the generation of a free edge in the absence of cell damage (Block et al, 2004). Such activation through EGFR depends on the heparin-binding, epidermal growth factor-like, growth factor (HB-EGF) pathway.…”

Section: Discussionmentioning

confidence: 99%