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MMP7 shedding of syndecan-1 facilitates re-epithelialization by affecting alpha(2)beta(1) integrin activation.

Chen P, Abacherli LE, Nadler ST, Wang Y, Li Q, Parks WC - PLoS ONE (2009)

Bottom Line: Because inflammation and repair are related events, we evaluated the role of syndecan-1 shedding in lung re-epithelialization.Additionally, we found that syndecan-1 augmented cell adhesion to collagen by controlling the affinity state of the alpha(2)beta(1) integrin.MMP7 acts in the lungs to regulate inflammation and repair, and our data now show that both these functions are controlled through the shedding of syndecan-1.

View Article: PubMed Central - PubMed

Affiliation: Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA. petechen@u.washington.edu

ABSTRACT

Background: Lung injury promotes the expression of matrix metalloproteinase-7 (MMP7, matrilysin), which is required for neutrophil recruitment and re-epithelialization. MMP7 governs the lung inflammatory response through the shedding of syndecan-1. Because inflammation and repair are related events, we evaluated the role of syndecan-1 shedding in lung re-epithelialization.

Methodology/principal finding: Epithelial injury induced syndecan-1 shedding from wild-type epithelium but not from Mmp7(-/-) mice in vitro and in vivo. Moreover, cell migration and wound closure was enhanced by MMP7 shedding of syndecan-1. Additionally, we found that syndecan-1 augmented cell adhesion to collagen by controlling the affinity state of the alpha(2)beta(1) integrin.

Conclusion/significance: MMP7 shedding of syndecan-1 facilitates wound closure by causing the alpha(2)beta(1) integrin to assume a less active conformation thereby removing restrictions to migration. MMP7 acts in the lungs to regulate inflammation and repair, and our data now show that both these functions are controlled through the shedding of syndecan-1.

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Syndecan-1 restrains lung re-epithelialization.(A) Wild-type and Sdc1−/− ALI cultures were wounded, and the repair was quantified. Each experiment was performed in triplicate and repeated at least 6 times. Original magnification×100. *p<0.0005 by Student's T-Test. (B) Wild-type and Sdc1−/− mice 4 days after naphthalene injury were processed for (B) H&E staining and (C) CCSP immunostaining (scale bar = 100 µm). Each panel is from a different mouse and has an accompanying enlarged portion of the airway (i.e., airways from 3 different mice were shown). In H&E stained sections, Sdc1−/− airway epithelium was more cuboidal in appearance. In contrast, wild-type epithelium was predominantly squamous with persistently exposed substratum (arrows). Additionally, the number of CCSP+cells per linear length of basement membrane (BM) along the airways (asterisk) was determined to quantify the epithelial repair after naphthalene injury. n = 4 mice, *p<0.01 by Student's T-Test.
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pone-0006565-g002: Syndecan-1 restrains lung re-epithelialization.(A) Wild-type and Sdc1−/− ALI cultures were wounded, and the repair was quantified. Each experiment was performed in triplicate and repeated at least 6 times. Original magnification×100. *p<0.0005 by Student's T-Test. (B) Wild-type and Sdc1−/− mice 4 days after naphthalene injury were processed for (B) H&E staining and (C) CCSP immunostaining (scale bar = 100 µm). Each panel is from a different mouse and has an accompanying enlarged portion of the airway (i.e., airways from 3 different mice were shown). In H&E stained sections, Sdc1−/− airway epithelium was more cuboidal in appearance. In contrast, wild-type epithelium was predominantly squamous with persistently exposed substratum (arrows). Additionally, the number of CCSP+cells per linear length of basement membrane (BM) along the airways (asterisk) was determined to quantify the epithelial repair after naphthalene injury. n = 4 mice, *p<0.01 by Student's T-Test.

Mentions: The observations that migration and syndecan-1 shedding were diminished in Mmp7−/− tissue and cells after injury suggested that release of syndecan-1 is needed to promote re-epithelialization. To study this idea, we injured syndecan-1 (Sdc1−/−) ALI cultures, which grew and differentiated indistinguishable from WT cultures, and found wounds closed significantly faster than in WT cultures (Figure 2A). Additionally, following naphthalene injury, re-epithelialization in vivo was quantitatively faster in Sdc1−/− mice with cuboidal cells appearing sooner compared to WT airways, in which the lining remained patchy and squamated at this time (Figure 2B). To quantify repair in vivo, we immunostained for Clara-cell specific protein (CCSP) and found the number of CCSP-positive cells along the airways was 2.5 times greater in Sdc1−/− mice at 4 days post-naphthalene compared to WT mice (Figure 2C). The airway epithelium in WT and Sdc1−/− mice was equivalent in vehicle-injected controls and had similar degrees of injury after naphthalene injury (data not shown). The accelerated wound closure in Sdc1−/− cultures and airways indicate that MMP7 shedding of syndecan-1 releases restrictions to epithelial cell movement.


MMP7 shedding of syndecan-1 facilitates re-epithelialization by affecting alpha(2)beta(1) integrin activation.

Chen P, Abacherli LE, Nadler ST, Wang Y, Li Q, Parks WC - PLoS ONE (2009)

Syndecan-1 restrains lung re-epithelialization.(A) Wild-type and Sdc1−/− ALI cultures were wounded, and the repair was quantified. Each experiment was performed in triplicate and repeated at least 6 times. Original magnification×100. *p<0.0005 by Student's T-Test. (B) Wild-type and Sdc1−/− mice 4 days after naphthalene injury were processed for (B) H&E staining and (C) CCSP immunostaining (scale bar = 100 µm). Each panel is from a different mouse and has an accompanying enlarged portion of the airway (i.e., airways from 3 different mice were shown). In H&E stained sections, Sdc1−/− airway epithelium was more cuboidal in appearance. In contrast, wild-type epithelium was predominantly squamous with persistently exposed substratum (arrows). Additionally, the number of CCSP+cells per linear length of basement membrane (BM) along the airways (asterisk) was determined to quantify the epithelial repair after naphthalene injury. n = 4 mice, *p<0.01 by Student's T-Test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2719060&req=5

pone-0006565-g002: Syndecan-1 restrains lung re-epithelialization.(A) Wild-type and Sdc1−/− ALI cultures were wounded, and the repair was quantified. Each experiment was performed in triplicate and repeated at least 6 times. Original magnification×100. *p<0.0005 by Student's T-Test. (B) Wild-type and Sdc1−/− mice 4 days after naphthalene injury were processed for (B) H&E staining and (C) CCSP immunostaining (scale bar = 100 µm). Each panel is from a different mouse and has an accompanying enlarged portion of the airway (i.e., airways from 3 different mice were shown). In H&E stained sections, Sdc1−/− airway epithelium was more cuboidal in appearance. In contrast, wild-type epithelium was predominantly squamous with persistently exposed substratum (arrows). Additionally, the number of CCSP+cells per linear length of basement membrane (BM) along the airways (asterisk) was determined to quantify the epithelial repair after naphthalene injury. n = 4 mice, *p<0.01 by Student's T-Test.
Mentions: The observations that migration and syndecan-1 shedding were diminished in Mmp7−/− tissue and cells after injury suggested that release of syndecan-1 is needed to promote re-epithelialization. To study this idea, we injured syndecan-1 (Sdc1−/−) ALI cultures, which grew and differentiated indistinguishable from WT cultures, and found wounds closed significantly faster than in WT cultures (Figure 2A). Additionally, following naphthalene injury, re-epithelialization in vivo was quantitatively faster in Sdc1−/− mice with cuboidal cells appearing sooner compared to WT airways, in which the lining remained patchy and squamated at this time (Figure 2B). To quantify repair in vivo, we immunostained for Clara-cell specific protein (CCSP) and found the number of CCSP-positive cells along the airways was 2.5 times greater in Sdc1−/− mice at 4 days post-naphthalene compared to WT mice (Figure 2C). The airway epithelium in WT and Sdc1−/− mice was equivalent in vehicle-injected controls and had similar degrees of injury after naphthalene injury (data not shown). The accelerated wound closure in Sdc1−/− cultures and airways indicate that MMP7 shedding of syndecan-1 releases restrictions to epithelial cell movement.

Bottom Line: Because inflammation and repair are related events, we evaluated the role of syndecan-1 shedding in lung re-epithelialization.Additionally, we found that syndecan-1 augmented cell adhesion to collagen by controlling the affinity state of the alpha(2)beta(1) integrin.MMP7 acts in the lungs to regulate inflammation and repair, and our data now show that both these functions are controlled through the shedding of syndecan-1.

View Article: PubMed Central - PubMed

Affiliation: Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA. petechen@u.washington.edu

ABSTRACT

Background: Lung injury promotes the expression of matrix metalloproteinase-7 (MMP7, matrilysin), which is required for neutrophil recruitment and re-epithelialization. MMP7 governs the lung inflammatory response through the shedding of syndecan-1. Because inflammation and repair are related events, we evaluated the role of syndecan-1 shedding in lung re-epithelialization.

Methodology/principal finding: Epithelial injury induced syndecan-1 shedding from wild-type epithelium but not from Mmp7(-/-) mice in vitro and in vivo. Moreover, cell migration and wound closure was enhanced by MMP7 shedding of syndecan-1. Additionally, we found that syndecan-1 augmented cell adhesion to collagen by controlling the affinity state of the alpha(2)beta(1) integrin.

Conclusion/significance: MMP7 shedding of syndecan-1 facilitates wound closure by causing the alpha(2)beta(1) integrin to assume a less active conformation thereby removing restrictions to migration. MMP7 acts in the lungs to regulate inflammation and repair, and our data now show that both these functions are controlled through the shedding of syndecan-1.

Show MeSH
Related in: MedlinePlus