Distinctive Integrin Expression in the Newly Forming Epidermis During Wound Healing in Humans

Cavani, Andrea; Zambruno, Giovanna; Marconi, Alessandra; Manca, V.; Marchetti, Maurizio; Giannetti, Alberto

doi:10.1111/1523-1747.ep12366057

Cited by 195 publications

(148 citation statements)

References 44 publications

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“…3A). As described previously (40), in wound healing and in organotypic cultures, a faint labeling of the lateral and apical surfaces of the basal and first suprabasal cell layer was observed (Fig. 3A).…”

Section: Resultssupporting

confidence: 81%

Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

Dellambra¹,

Prislei²,

Salvati³

et al. 2001

Journal of Biological Chemistry

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The cytoplasmic domain of ␤ 4 integrin contains two pairs of fibronectin-like repeats separated by a connecting segment. The connecting segment harbors a putative tyrosine activation motif in which tyrosines 1422 and 1440 are phosphorylated in response to ␣ 6 ␤ 4 binding to laminin-5. Primary ␤ 4 -null keratinocytes, obtained from a newborn suffering from lethal junctional epidermolysis bullosa, were stably transduced with retroviruses carrying a full-length ␤ 4 cDNA or a ␤ 4 cDNA with phenylalanine substitutions at Tyr-1422 and Tyr-1440. Hemidesmosome assembly was evaluated on organotypic skin cultures. ␤ 4 -corrected keratinocytes were indistinguishable from normal cells in terms of ␣ 6 ␤ 4 expression, the localization of hemidesmosome components, and hemidesmosome structure and density, suggesting full genetic and functional correction of ␤ 4 -null keratinocytes. In cultures generated from ␤ 4 Y1422F/Y1440Fkeratinocytes, ␤ 4 mutants as well as ␣ 6 integrin, HD1/ plectin, and BP180 were not concentrated at the dermalepidermal junction. Furthermore, the number of hemidesmosomes was strikingly reduced as compared with ␤ 4 -corrected keratinocytes. The rare hemidesmosomes detected in ␤ 4 Y1422F/Y1440F cells were devoid of subbasal dense plates and of inner cytoplasmic plaques with keratin filament insertion. Collectively, our data demonstrate that the ␤ 4 tyrosine activation motif is not required for the localization of ␣ 6 ␤ 4 at the keratinocyte plasma membrane but is essential for optimal assembly of bona fide hemidesmosomes.Human epidermis consists of a stratified squamous epithelium composed of keratinocytes organized in distinct cellular layers. Keratinocytes forming the basal layer firmly adhere to the basement membrane by means of hemidesmosomes (HDs), 1 multiprotein complexes linking the epithelial intermediate filament network to the dermal anchoring fibrils (see Refs. 1 and 2 for review). HDs are formed by the clustering of several cytoplasmic and trans-membrane proteins (2). The cytoplasmic HD plaque components, which include HD1/plectin (3) and the bullous pemphigoid antigen 1 (BP230) (4), act as linkers for elements of the cytoskeleton at the cytoplasmic surface of plasma membrane. The trans-membrane constituents of HDs, which include the ␣ 6 ␤ 4 integrin (5, 6) and the bullous pemphigoid antigen 2 (BP180) (7), serve as cell receptors connecting the cell interior to extracellular matrix proteins.In particular, the ␣ 6 ␤ 4 integrin is a receptor for the basement membrane component laminin-5, a heterotrimeric protein composed of three distinct polypeptides, ␣3, ␤3, and ␥2, which are encoded by three different genes known as LAMA3, LAMB3, and LAMC2, respectively (see Ref. 8 for review). Laminin-5 binds to the basal keratinocyte cell surface through the ␣ 6 ␤ 4 integrin and tightens the dermal-epidermal junction by binding also to the N-terminal NC-1 domain of type VII collagen (9). The crucial importance of the interaction between laminin-5 and its ␣ 6 ␤ 4 receptor in maintaining the integrity of the i...

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Section: Resultssupporting

confidence: 81%

Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

Dellambra¹,

Prislei²,

Salvati³

et al. 2001

Journal of Biological Chemistry

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“…These findings were not surprising. Grinnell and co-workers demonstrated that keratinocytes freshly isolated from skin do not adhere to fibronectin (35), and keratinocytes in intact skin do not express ␣5␤1 or the ␣v subunit (33,36), the integrins that bind fibronectin and fibrin, respectively (34). As for ␣v␤5, ␣5␤1 is induced in response to wounding and is expressed on the basal surface of the same population of keratinocytes producing collagenase-1 (3).…”

Section: Discussionmentioning

confidence: 99%

Induction and Repression of Collagenase-1 by Keratinocytes Is Controlled by Distinct Components of Different Extracellular Matrix Compartments

Sudbeck¹,

Pilcher²,

Welgus³

et al. 1997

Journal of Biological Chemistry

108

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In all forms of cutaneous wounds, collagenase-1 (matrix metalloproteinase-1 (MMP-1)) is invariably expressed by basal keratinocytes migrating over the dermal matrix. We report that native type I collagen mediates induction of MMP-1 by primary human keratinocytes. Collagen-mediated induction of MMP-1 was rapid, being detected 2 h after plating, and was transcriptionally regulated. As demonstrated by in situ hybridization, only migrating keratinocytes expressed MMP-1, suggesting that contact with collagen is not sufficient to induce MMP-1 expression in keratinocytes; the cells must also be migrating. Upon denaturation, type I collagen lost its ability to induce MMP-1 expression but still supported cell adhesion. Other dermal or wound matrix proteins, such as type III collagen, fibrin, and fibronectin, and a mixture of basement membrane proteins did not induce MMP-1 production. In the presence of collagen, laminin-1 inhibited induction of MMP-1 but laminin-5 did not. Taken together, these observations suggest that as basal keratinocytes migrate from the basal lamina onto the dermal matrix contact with native type I collagen induces MMP-1 expression. In addition, our findings suggest that re-establishment of the basement membrane and, in particular, contact with laminin-1 provides a potent signal to down-regulate MMP-1 production as the epithelium is repaired.Normal cutaneous wound healing, as well as healing in essentially all tissues, involves an orderly progression of events to re-establish the integrity of the injured tissue. The initial injury starts a programmed series of interdependent yet functionally separate responses, such as re-epithelialization and epithelial proliferation, inflammation, angiogenesis, fibroplasia, matrix accumulation, and eventually resolution. During each stage in this process, proteinases are needed to remove or remodel extracellular matrix components in both the epithelial and interstitial compartments to accommodate cell migration and tissue repair (1).In a thorough examination of normally healing wounds and of a variety of chronic ulcers, we found that collagenase-1, a member of the matrix metalloproteinase (MMP) 1 family with the ability to cleave fibrillar collagens type I, II, and III at a specific locus in their triple helical domain, is invariably expressed by basal keratinocytes at the edge of repairing tissue (2-4). In all, we have examined Ͼ100 different human skin specimens, representing a variety of chronic ulcers, blisters, and normally healing wounds, and in each sample with injury that breached the basement membrane, collagenase-1 was prominently and invariantly expressed by basal keratinocytes migrating over the dermal wound bed. The invariable expression of collagenase-1 in all forms of wounds and the confinement of its expression to periods of active re-epithelialization suggest that this enzyme plays a critical role in keratinocyte function during healing. Indeed, we recently demonstrated that keratinocyte migration on a native collagen matrix requires the catalyti...

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“…We further examined whether 64 integrin is involved in keratinocyte locomotion. Because of the limited access of inhibitory antibodies to the basal surface of cells in the colony, we investigated keratinocyte movements in two-dimensional cell aggregates, which were formed after high and Wilgram, 1973;Cavani et al, 1993). Although directed migration is indispensable for wound closure, collective motion generated by keratinocyte stem cells might also be involved in epidermal wound healing.…”

Section: 64 Integrin Is Required For Collective Motionmentioning

confidence: 99%

Cell motion predicts human epidermal stemness

Nanba

Toki

Tate

et al. 2016

Journal of Dermatological Science

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Distinctive Integrin Expression in the Newly Forming Epidermis During Wound Healing in Humans

Cited by 195 publications

References 44 publications

Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

Induction and Repression of Collagenase-1 by Keratinocytes Is Controlled by Distinct Components of Different Extracellular Matrix Compartments

Cell motion predicts human epidermal stemness

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