Keratinocytes freshly isolated from unwounded skin could not attach and spread on fibronectin (FN)-coated culture dishes and could not bind and phagocytose FN-coated beads. These adhesive functions were activated, however, in Keratinocytes that were isolated from healing wounds. Moreover, adhesiveness of basal Keratinocytes to FN substrata was activated during epidermal cell or explant culture. Activation was specific for attachment to FN compared to other adhesion ligands, and occurred even when epidermal cells were cultured on collagen, basement membrane matrix, or lectin-coated substrata. Biochemical studies showed that Keratinocytes have a 140× 103Mr FN receptor analogous to the fibroblast receptor for FN, and that this receptor is expressed in activated Keratinocytes but not in Keratinocytes freshly isolated from unwounded skin. The absence of FN receptors from Keratinocytes in unwounded skin is not surprising since the basal Keratinocytes of the epidermis are attached to a basement membrane containing laminin and type IV collagen. During wound repair, however, these cells migrate over or through a FN-coated matrix. Consequently, expression of FN receptors may be an essential feature of healing. Believing that FN is the required substratum for keratinocyte migration during wound healing, we have initiated clinical studies to determine if topical application of FN is useful as a therapy for non-healing cutaneous ulcers.

In recent years, research concerning cell-substratum adhesion has focused on the identification of extracellular ligands that mediate adhesion and on the cell surface receptors with which these ligands interact (reviewed by Grinnell, 1978; Yamada, 1983). To understand the physiological functions and specificity of adhesive interactions, however, it will be necessary to analyse the topographical distribution and temporal expression of adhesion ligands and their receptors in situ. Consequently, we have become interested in the wound-repair process, since this involves changes in cell adhesion and motility as well as changes in the extracellular matrices with which the cells interact (Grinnell, 1984). For instance, basal Keratinocytes in unwounded skin exist as stationary cells attached to a basement membrane that contains laminin and type IV collagen (Katz, 1984). But during wound repair, these cells migrate over or through a fibronectin (FN)-coated matrix (Grinnell et al. 1981 ; Clark et al. 1982) in the absence of laminin and type IV collagen (Stanley et al. 1981). In this brief review, we describe our recent findings on the adhesion of Keratinocytes to FN and other adhesion ligands and on the modulation of keratinocyte adhesiveness that occurs during wound healing.

In vitro activation of keratinocyte FN receptor function

Several years ago it was suggested that laminin was the adhesion ligand specific for epidermal cells (Terranova et al. 1980; Kleinman et al. 1981), but other studies did not support this idea (Gilchrest et al. 1982; Stennet al. 1983). Subsequently, we and others examined the adhesive properties of cultured human epidermal cells and found that FN was indeed an adhesion ligand for these cells that promoted not only cell attachment and spreading, but also, phagocytosis and motility (Takashima & Grinnell, 1984, 1985; O’Keefe et al. 1985; Clark et al. 1985). Moreover, FN also promoted the migration of corneal epithelial cells (Nishida et al. 1985).

In the course of our experiments, we found that epidermal cells freshly isolated from human skin, unlike cultured cells, were unable to attach to FN substrata in short-term (45 min) assays (Takashima & Grinnell, 1985). Subsequently, we studied the onset of FN adhesion function during epidermal cell culture. After different periods of culture, cells were harvested using the same combination of dispase and trypsin treatments used to harvest cells from skin. Then, the adhesiveness of the harvested, cultured cells was tested in short-term assays on FN-coated substrata (Fig. 1). In contrast to freshly isolated cells or cells from 2- or 4-day cultures, about 25 % of the cells harvested from 7-day cultures were able to attach, and 75 % of the attached cells were spread. Adhesiveness to FN reached its maximal level in cells harvested from 10-day cultures. The activated epidermal cells were found to be basal Keratinocytes, on the basis of indirect immunofluorescence staining with bullous pemphigoid (BP) serum. It should be noted that the onset of adhesiveness to FN occurred similarly in medium that contained complete serum or FN-depleted serum. Therefore, the activation effect was not simply a consequence of increasing the level of exogenous FN in the medium to which the cells were exposed.

Fig. 1.

Initiation of FN-mediated cell attachment and spreading during cell culture. Human epidermal cells were freshly isolated or cultured in medium with complete serum or FN-depleted serum. At the times indicated, the cells were harvested by treatment with dispase and trypsin, after which attachment and spreading on FN substrata were measured in 45-min assays. Data shown are the means ± from duplicate experiments. For details see Takashima & Grinnell (1985). (◼,◻) Control serum; (•,○) pFN-depleted serum.

Fig. 1.

Initiation of FN-mediated cell attachment and spreading during cell culture. Human epidermal cells were freshly isolated or cultured in medium with complete serum or FN-depleted serum. At the times indicated, the cells were harvested by treatment with dispase and trypsin, after which attachment and spreading on FN substrata were measured in 45-min assays. Data shown are the means ± from duplicate experiments. For details see Takashima & Grinnell (1985). (◼,◻) Control serum; (•,○) pFN-depleted serum.

To test whether the activation of keratinocyte FN receptor function was a consequence of dissociated cell culture, studies were performed with epidermal explant cultures. Skin explants were maintained for 9 days, during which time extensive outgrowth of epidermal cells occurred. Then the cells from the central explant region and the migration region were harvested separately and tested for adhesion (Table 1). Consistent with the above results, Keratinocytes that had migrated out of the skin explants were enhanced markedly in their attachment and spreading on FN substrata compared with non-motile Keratinocytes that remained behind.

Table 1.

Plasma FN-mediated attachment and spreading of cells in explant cultures

Plasma FN-mediated attachment and spreading of cells in explant cultures
Plasma FN-mediated attachment and spreading of cells in explant cultures

Activation of keratinocyte adhesion to FN in vivo

We also analysed the activation of FN receptor function during wound healing in vivo (Takashima et al. 1986). In these studies, rabbit ear epidermal cells were. transplanted onto full-thickness wound beds that had been prepared on the backs of the same rabbits (Fig. 2). At various times after transplantation, biopsy samples were taken from the wound beds, and cells harvested from the biopsies were tested for adhesion to FN. Keratinocytes in the biopsy samples were identified by indirect immunofluorescence staining with anti-keratin antibodies (Fig. 3). It was found that Keratinocytes harvested from 3-day grafts were able to attach and spread on FN substrata (Fig. 3A,B), unlike Keratinocytes freshly harvested from ear skin (Fig. 3C,D).

Fig. 2.

Autotransplantation model to study re-epithelialization of full-thickness wounds. Rabbit ear epidermal cells were transplanted onto full-thickness wound beds that had been prepared on the backs of thesame rabbits. At various times after transplantation, biopsy samples were taken from the wound beds, and cells harvested from the biopsies were tested for attachment and spreading on FN substrata in 2-h assays. For details see Takashima et al. (1986).

Fig. 2.

Autotransplantation model to study re-epithelialization of full-thickness wounds. Rabbit ear epidermal cells were transplanted onto full-thickness wound beds that had been prepared on the backs of thesame rabbits. At various times after transplantation, biopsy samples were taken from the wound beds, and cells harvested from the biopsies were tested for attachment and spreading on FN substrata in 2-h assays. For details see Takashima et al. (1986).

Fig. 3.

Antibody identification of cells attached to FN substrata (see Fig. 2). A,B. Cells harvested 3 days after transplantation; C,D. Cells freshly isolated from rabbit ear skin. At the end of adhesion assays, cells were fixed, permeabilizcd and processed for indirect immunofluorescence with anti-keratin antibodies. Most cells harvested from the 3-dav transplant sites were keratinocvtes that spread well on the dishes (A,B). Nonkeratinocytes were detected by the lack of keratin staining (A, arrow). Freshly isolated keratinocvtes attached to the dishes loosely and did not spread (C,D). X700. For details see Takashima el at. (1986).

Fig. 3.

Antibody identification of cells attached to FN substrata (see Fig. 2). A,B. Cells harvested 3 days after transplantation; C,D. Cells freshly isolated from rabbit ear skin. At the end of adhesion assays, cells were fixed, permeabilizcd and processed for indirect immunofluorescence with anti-keratin antibodies. Most cells harvested from the 3-dav transplant sites were keratinocvtes that spread well on the dishes (A,B). Nonkeratinocytes were detected by the lack of keratin staining (A, arrow). Freshly isolated keratinocvtes attached to the dishes loosely and did not spread (C,D). X700. For details see Takashima el at. (1986).

Quantification of the results (Fig. 4) showed that there was a dramatic increase in the ability of Keratinocytes to attach and spread on FN substrata, and this activity reached a maximum in cells isolated from the graft bed 3 days after transplantation. A similar activation occurred in the ability of cells to bind and phagocytose FN- coated beads. Subsequently, FN receptor function returned towards the resting level in cells isolated around the same time that the epidermis was reconstituted. These results led us to suggest that activation of keratinocyte FN receptor function might be necessary for migration of Keratinocytes through the wound matrix.

Fig. 4.

Attachment and spreading activity of freshly isolated and transplanted keratinocytes (see Fig. 2). Data shown are the means ± s.D. from duplicate experiments. For details see Takashima et al. (1986).

Fig. 4.

Attachment and spreading activity of freshly isolated and transplanted keratinocytes (see Fig. 2). Data shown are the means ± s.D. from duplicate experiments. For details see Takashima et al. (1986).

Specificity of keratinocyte adhesion to FN

One explanation for the activation of keratinocyte adhesion to FN was a general increase in cell adhesiveness. To test this possibility, we studied the ability of freshly isolated and cultured cells to attach to substrata other than FN (Toda & Grinnell, 1987). The other substrata tested were laminin and type IV collagen-containing basement membrane matrix produced by FIR-9 cells, collagen (95 % type I), and the lectins concanavalin A and wheat-germ agglutinin. Freshly isolated epidermal cells were able to attach to basement membrane matrix, collagen and lectins (‘Fable 2). It could be concluded, therefore, that these cells had adhesion receptors for ligands other than FN. Significantly, however, no spreading of the attached cells was observed on any of the adhesion ligands.

About 28 % of the cells in the freshly isolated epidermal preparations were basal Keratinocytes. Of the cells that attached to basement membrane matrix and collagen- coated substrata, however, about 80% were BP-positive (Table 2). Therefore, more than 90% of the basal cells in the preparation had attached to these substrata. The selective attachment of basal Keratinocytes to collagen substrata was also found by others (Stanley et al. 1980). The lectin-coated substrata, on the other hand, were not selective for basal Keratinocytes since the percentage of basal cells that attached to these substrata was the same as the percentage of these cells in the epidermal preparation (Table 2).

Table 2.

Adhesion of freshly isolated epidermal cells to various substrata

Adhesion of freshly isolated epidermal cells to various substrata
Adhesion of freshly isolated epidermal cells to various substrata

The adhesiveness of cultured epidermal cells to substrata other than FN also was tested (big. 5). Unlike cell attachment to FN-coated substrata, there was little change in the ability of cultured cells to attach to collagen or lectin-coated substrata. That is, the extent of cell attachment measured with freshly isolated cells (Fig. 5, day 0) was similar to the extent of cell attachment measured with cells harvested from 9-day cultures or 22-day cultures. Similar results were obtained for cell attachment to basement membrane matrix. Since there was an increase in cell attachment to FN- coated substrata but not to the other ligand-coated substrata, we concluded that the activation of cell attachment to FN was specific.

Fig. 5.

Attachment of freshly isolated and cultured epidermal cells to various substrata. Human epidermal cells, freshly isolated or cultured on plastic for the times indicated, were harvested and incubated for 45 min on the substrata shown (6 dishes per experiment). Data shown are for cell attachment and are theaverages and s .d. from four separate experiments. For details see Toda & Grinnell (1987).(○)ConA;(◻)WGA;(•)collagen;(◼)FN. See Table 2 for abbreviations.

Fig. 5.

Attachment of freshly isolated and cultured epidermal cells to various substrata. Human epidermal cells, freshly isolated or cultured on plastic for the times indicated, were harvested and incubated for 45 min on the substrata shown (6 dishes per experiment). Data shown are for cell attachment and are theaverages and s .d. from four separate experiments. For details see Toda & Grinnell (1987).(○)ConA;(◻)WGA;(•)collagen;(◼)FN. See Table 2 for abbreviations.

In addition to the selective activation of FN attachment activity, we observed a coordinated pattern of cell spreading activation that was independent of the substratum (Fig. 6). That is, freshly isolated cells did not spread on any of the adhesion ligands tested, but more than 50% of the cells harvested from 4-day cultures were able to spread. With cells that were harvested from 9-day cultures, about 80% of the cells that attached were observed to spread. On the basis of the simultaneous onset of cell spreading activity that was independent of the ligand on the substratum, it seemed likely this was a general activation process.

Fig. 6.

Spreading of freshly isolated and cultured epidermal cells on various substrata. Same as Fig. 5 except the data shown are for cell spreading.

Fig. 6.

Spreading of freshly isolated and cultured epidermal cells on various substrata. Same as Fig. 5 except the data shown are for cell spreading.

Samples from the experiments with cultured cells were also analysed to determine the percentage of attached cells that were basal Keratinocytes. Most of the cells harvested from 22-day cultures that attached to FN and collagen substrata were basal cells (80—90 %), but basal cells accounted for only about 50 % of the epidermal cells in these cultures. It coúld be concluded, therefore, that cultured basal cells attached selectively to FN and collagen-coated substrata.

As already mentioned above, keratinocyte adhesiveness to FN was activated if FN- depleted serum was used in the cell cultures. We also measured keratinocyte adhesion to FN, collagen and basement membrane matrix after culturing cells on these substrata. The chemical composition of the substratum on which the cells were cultured, however, did not appear to affect the subsequent adhesiveness of the cells (Table 3).

Analysis of keratinocyte FN receptors

To learn more about the mechanisms underlying activation of keratinocyte adhesion to FN, we analysed keratinocyte FN receptors (Toda et al. 1987). In the presence of the peptide Gly-Arg-Gly-Asp-Ser-Pro-Cys, which is known to compete for the FN cell-binding domain (Pierschbacher & Ruoslahti, 1984; Yamada & Kennedy, 1984), we found that keratinocyte adhesion to FN but not to collagen was inhibited. Also, keratinocyte adhesion to FN but not to collagen was inhibited by polyclonal antibodies to the 140×103Mr FN receptors of Chinese hamster ovary cells (Brown & Juliano, 1986). Consequently, it seems likely that the keratinocyte FN receptor is similar to the fibroblast FN receptor that has been described by others (Neff et al. 1982; Pytela et al. 1985; Brown & Juliano, 1985) and called integrin (Tamkun et al. 1986; and see Buck & Horwitz, this volume).

The molecular composition of keratinocyte receptors was analysed in two ways. First, metabolically radiolabelled, cultured Keratinocytes were extracted with detergent, and the extracts were chromatographed on antibody columns prepared with non-immune IgG or anti-140× 103MT FN receptor IgG. The results of these studies showed that a single cellular component (molecular mass about 140×103) bound to the immune column (Toda et al. 1987). Also, the non-immune and immune IgGs were used to immunoprecipitate cell extracts prepared from freshly isolated and cultured Keratinocytes. A polypeptide of approximately 140×103Mr was detected in extracts from cultured cells but not in extracts from freshly isolated cells. It seems likely, therefore, that cultured Keratinocytes were activated to express the 140K (K = X103Mr) FN receptors. Additional evidence favouring this interpretation is that cultured Keratinocytes but not freshly isolated Keratinocytes were able to absorb the adhesion inhibition activity from the anti-140K FN receptor IgG preparation, and that cultured Keratinocytes but not freshly isolated Keratinocytes were able to attach to culture dishes coated with the anti-140K FN receptor IgG preparation (Toda et al. 1987).

Fibronectin as a therapeutic reagent

On the basis of our studies summarized above and those reported by others, we believe that FN is the matrix component that promotes keratinocyte adhesion and migration during wound repair (cf. Woodley et al. 1985). Consequently, one explanation for deficient healing of poorly vascularized wounds is that they lack sufficient FN or that FN in the wounds is degraded. In support of this idea, preliminary studies have shown that topical application of FN can promote healing of corneal ulcers (Nishidaet al. 1985; Kono et al. 1985). To analyse further the possible therapeutic benefit of FN, we have initiated a double-blind, controlled clinical study in which topical FN is being used to treat non-healing decubitus and stasis ulcers. Although insufficient data have been collected to reach general conclusions, one patient who has been treated with topical FN for an extended period of time has shown a dramatic improvement. This patient had bilateral stasis ulcers that had resisted both routine and experimental treatments for more than 5 years. At the end of the 3-week period of the clinical trial, the patient requested continued FN therapy since one of her ulcers was improved. The improved ulcer was the one that had been treated with FN, and subsequently the patient was treated with FN on both ulcers. After 4 months, one ulcer had healed almost completely, and the other was improved more than 50% (Wysocki et al. 1987).

Cell adhesion during wound repair appears to be a paradigmatic example of how adhesion specificity is determined by the topographical distribution and temporal expression of adhesion ligands and their receptors in situ. Keratinocytes from unwounded skin lack FN receptors, but these receptors are expressed transiently during wound repair at the same time as there is a transient change in the extracellular matrix from a laminin and type IV collagen-containing basement membrane to a FN-coated matrix. Thus, the wound-healing situation modulates keratinocyte FN receptor expression.

The precise signal that turns expression of FN receptors on and off during wound healing is unknown. Probably, however, the change in extracellular matrix from laminin and type IV collagen to FN is not the key feature. This can be concluded since epidermal cells cultured on serum-coated plastic, fibronectin, collagen type I and basement membrane matrix were all activated to the same extent in their adhesiveness to FN. More probably, the loss of contact inhibition of the intact epidermal layer has pleotropic effects leading to increased cell motility and division (Rosen & Misfeldt, 1980), and one of these effects is the expression of FN receptors.

Changes in the expression of FN receptors -have also been reported during development. In murine erythroleukaemia cells, for instance, it was found that the 140K FN receptors disappeared after dimethyl sulphoxide-induced differentiation of these cells (Patel & Lodish, 1986). Consistent with this finding, reticulocytes but not erythrocytes from peripheral blood express the 140K receptors. Thus, loss of the receptors may be a feature of terminal differentiation during haematopoiesis. In another study, it was found that the 140K FN receptor was present on embryonic chick lung cells, but markedly reduced in differentiated cells except smooth muscle (Chen et al. 1986). Future studies will be necessary to determine whether similar molecular mechanisms control developmental changes in FN receptor expression and the modulation of FN receptor expression during wound repair.

We are indebted to Dr William Snell for his helpful comments regarding this manuscript. This research has been supported by a grant from the NIH (GM31321).

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