In his “Harvey Lecture” on wound repair, presented more than 30 years ago, Paul Weiss (1959) described kératinocyte migration this way:

[When] skin is injured, the bobbins of cells near the wound give up their hold, the binding layer becomes free, and the whole cell, deprived of its moorings, rolls and glides off in a sort of ameboid motion. Its migratory phase begins. This makes us ask at once, what actuates these cells to change from sedentary to migratory life?

Modem cell biology is on the verge of answering Weiss’s question. Recent studies have identified the adhesion systems that participate in ‘bobbins’ (i.e., hemidesmosomes) and the changes in adhesion receptors that can account for kératinocyte activation, that is, the transition of keratinocytes from a sedentary to migratory lifestyle. In this commentary, I will review some of the recent research on changes that occur during activation of normal keratinocytes to wound keratinocytes and discuss the role of integrin receptor modulation in these changes.

In normal skin, the epidermal layer attaches to the basement membrane, a complex zone containing a variety of different components including type IV collagen, laminin, and heparan sulfate proteoglycan (Furthmayr, 1988). Adhesion between keratinocytes and the basement membrane is specialized for mechanical stability. Resistance of these adhesions to hypertonic stress permitted Paul Weiss (1959) to identify the primary adhesion structures, which he called “bobbins”, and which were later named hemidesmosomes. Recent findings suggest that hemidesmosomes contain at least two adhesion systems: the bullous pemphigoid antigens (bpl80 and bp230) (Stanley et al., 1981; Mutasim et al., 1985) and integrin α6β4 receptors (Kajiji et al., 1989; Carter et al., 1990b; Sonnenberg et al., 1991). The α6β4 integrin receptor has been shown to mediate adhesion to laminin (De Luca et al., 1990), and bp antigens may interact with a variety of basement membrane components through their collagen-like domains (Giudice et al., 1991).

To date, the major β1 integrins reported in adult skin are α2β1 and α3β1These appear to be localized mostly along the lateral cell borders of keratinocytes (Kaufmann et al., 1989; Konter et al., 1989; Peltonen et al., 1989), where they may function in cell-cell adhesion (Kaufmann, 1989; Larjava et al., 1990; Marchisio et al., 1991). Whether these receptors mediate cell-matrix interactions in vivo as they do in vitro (Carter et al., 1990a; Staquet et al., 1990) remains to be determined. Most studies have shown an absence or low levels of expression in adult skin of the other β1 integrin receptors and α1β1, α4β1 and α5β1 (the fibronectin receptor). A detailed study on the timing of appearance of these receptors during human embryonic development showed that α1β1, α3β1 and α3β1were highly expressed during the first 15 weeks of gestation after which declined and α1β1 appeared (Hertle et al., 1991).

Early studies on keratinocyte adhesion in vitro showed that these cells could bind to a variety of matrix components including collagens, fibronectin, vitronectin and laminin (Stanley et al., 1980; Gilchrest et al., 1982; Stenn et al., 1983). No attempt was made, however, to compare the adhesion phenotype of freshly isolated cells with cultured cells. Table 1 summarizes a series of experiments from our laboratory, which were aimed at making just this comparison. Although basal keratinocytes in the epidermal cell population can attach to type I collagen or to lamininμype IV collagen-coated surfaces, the freshly harvested cells cannot spread or migrate. Moreover, these cells lack the ability to attach to fibronectin substrata or to phagocytose fibronectin-coated beads.

Table 1.

Activation of human kératinocyte adhesion during the first week of cell culture

Activation of human kératinocyte adhesion during the first week of cell culture
Activation of human kératinocyte adhesion during the first week of cell culture

Modulation of keratinocyte adhesion after wounding

Wounding of skin signals the transition of keratinocytes from a sedentary to migratory lifestyle. After disruption of the basement membrane, a fibronectin-rich wound interface (Grinnell et al., 1981) provides the provisional matrix for subsequent cell migration (Clark et al., 1982). To analyze changes in cell adhesion that occur after wounding, we grafted rabbit keratinocytes onto full thickness wound beds. After various times, the keratinocytes were re-isolated from the wounds and tested for their adhesiveness. Rabbit keratinocytes, freshly harvested from skin, cannot attach or spread on fibronectin surfaces or phagocytose fibronectin-coated beads, but these adhesive functions are activated in keratinocytes harvested from the wound. The extent of activation reaches maximal levels 3–4 days after grafting and subsequently declines after the integrity of the epidermis is re-established (Takashima et al., 1986).

Cultured human keratinocytes can also attach, spread and migrate on fibronectin surfaces and phagocytose fibronectin-coated beads (Takashima and Grinnell, 1984, O’Keefe et al., 1985; Clark et al., 1985). As shown in Table 1, these adhesion activities develop during the first week after placing cells in culture. Therefore, removing keratinocytes from skin and placing them in culture appears to provide the same activating signal as wounding.

Changes in integrin receptor expression accompany the changes in adhesion phenotype of activated keratinocytes. Integrin α5β1 fibronectin receptors can be observed in vivo in migrating epidermal cells (Clark, 1990). Similarly, keratinocytes migrating out of expiants in vitro expressed integrin β1 subunits at their basal surfaces as well as at lateral cell borders (Guo et al., 1990) and also expressed α5 subunits (Guo et al., 1991). Finally, increased synthesis of fibronectin receptors (Toda et al., 1987) and α3β1 receptors (Klein et al., 1987) were observed in cultured cells. On the other hand, decreased adhesion function accompanying terminal differentiation of keratinocytes occurred before loss of integrin receptors from the cell surface (Adams and Watt, 1990), and other factors besides receptor expression per se have been shown to be important in regulating adhesion binding interactions, e.g., receptor clustering (Detmers et al., 1987) and receptor conformation (Neugebauer and Reichardt, 1991; Du et al., 1991).

Recently, we learned that processing of β1 integrin subunits also occurs differently before and after kératinocyte activation. Cells freshly harvested from skin synthesize predominantly immature β1 integrin subunits, whereas cultured keratinocytes synthesize predominantly mature integrin subunits (Guo et al., 1991). Because only mature β1 integrins reach the cell surface (Akiyama and Yamada, 1987), the shift in processing results in a more than 10-fold increase in ft-containing integrin receptors on the surfaces of cultured keratinocytes compared to freshly harvested cells (unpublished observations).

Changes in β1 integrin receptor expression at the cell surface can account for the increased adhesive properties of cultured keratinocytes. Conversely, suprabasal keratinocytes attach poorly to fibronectin and collagen (Stanley et al., 1980; Takashima and Grinnell, 1984; Toda and Grinnell, 1987). Therefore, terminal differentiation of keratinocytes provides a model to study the in vitro reversion of keratinocytes from the activated phenotype (Adams and Watt, 1990;.Nicholson and Watt, 1991). An intriguing but as yet unexplained feature of this reversion is the loss of adhesion function several hours prior to the loss of adhesion receptors.

The studies described above emphasize β1 integrin receptors. Other adhesion interactions also may be involved in kératinocyte migration. Vitronectin promotes kératinocyte adhesion (Stenn et al., 1983) and migration (Brown et al., 1991), and increased levels of vitronectin can be found in some inflammatory skin conditions (Dahlback, 1989). keratinocytes adhesion to vitronectin probably depends on the integrin receptor avfi5, which also can promote adhesion to fibronectin (Cheresh et al., 1989; Marchisio et al., 1991). Thrombospondin, another protein found in the basement membrane (Wight et al., 1985), promotes kératinocyte adhesion and migration (Varani et al., 1986; Nickoloff et al., 1988), and is elevated transiently at the wound interface (Murphy-Ullrich and Mosher, 1985; Raugi et al., 1987). The kératinocyte receptor for thrombospondin has yet to be clearly identified and may be an integrin receptor (Lawler et al., 1988) or proteoglycan (Sun et al., 1989).

Keratinocytes activation

Keratinocytes activation likely involves not only modulation of β1 integrin receptors and cell adhesion, but also alteration of other kératinocyte functions (Mans-bridge and Knapp, 1987; Smoller et al., 1990). These include synthesis of hyperproliferative keratins (Sun et al., 1985) and urokinase-type plasminogen activator (Morioka et al., 1985; Grondahl-Hansen et al., 1988), and expression of functional interleukin 1 receptors (Blanton et al., 1989). In addition, there may be a second stage of kératinocyte activation that leads to the phenotype expressed by keratinocytes involved in chronic inflammatory diseases of the skin. Possible changes that characterize the inflammatory kératinocyte phenotype include synthesis of tissue plasminogen activator (Jensen et al., 1988), and expression of HLA-DR (Aubock et al., 1986) and ICAM-1 (integrin receptor αLβ2)(Dustin et al., 1988; Griffiths et al., 1989).

The signals that regulate kératinocyte activation are poorly understood. Weiss’s question - what actuates the change from a sedentary to migratory lifestyle - cannot yet be answered. Maximal activation of cultured kératinocyte adhesiveness requires loss of contact with the basement membrane (Guo et al., 1990) and depends on exposure of the cells to factors in serum (Kim and Grinnell, 1990). Since keratinocytes themselves produce a variety of cytokines and growth factors, regulation likely involves both autocrine and paracrine effects (McKenzie and Sauder, 1990). Polypeptide growth factors that influence kératinocyte migration include transforming growth factor a EGF, (Barrandon and Green, 1987) and transforming growth factor β (Hebda, 1988; Mansbridge and Hanawalt, 1988; Wikner et al., 1988). Also, keratinocytes can acquire the inflammatory phenotype in vitro in response to γ-interferon (Basham et al., 1984; Volc-Platzer et al., 1985).

Integrin modulation during wound healing

Understanding normal and pathological features of healing requires learning about modulation of cell adhesion and integrin receptor expression during wound repair. Studies on integrin modulation during wound healing also can lend some insight into the apparent redundancy of integrin receptors and their ligands. A recent commentary in Journal of Cell Science illustrates this redundancy (Humphries, 1990). In the five years since recognition of the integrin superfamily of adhesion receptors (Hynes, 1987), more than 14 integrin receptors have been identified, most of which interact with more than one adhesion ligand.

Studies aimed at determining specificity of receptorligand recognition depend typically on in vitro assays. Results of such assays reflect cellular potential for action, biological boundary conditions (Polanyi, 1968), what J.P. Trinkaus called the cells’ ‘repertoire’. Given this repertoire, the problem is to learn when and where different adhesion activities are expressed. Wound healing provides an ideal system in which to explore this problem because repair is a dynamic, cyclical process involving a series of transient changes in extracellular matrix and corresponding changes in cell adhesion interactions (Grinnell, 1984; Woodley et al., 1985; Clark, 1985).

Recent research on kératinocyte adhesion during wound repair addresses fundamental questions that Paul Weiss raised more than 30 years ago. The cartoon shown in Fig. 1 illustrates one aspect of integrin modulation associated with kératinocyte activation. Skin keratinocytes attach to the basement membrane (BM) by hemidesmosomes (triangles), which contain bp antigens and integrin α6β4 receptors; α5β1 integrin receptors either are not synthesized or are degraded inside the cells. After wounding, keratinocytes migrate on fibronectin (FN) using α5β1 integrin receptors (closed squares), now expressed at the cell surface. Activation of this process appears to depend on changes in the extracellular matrix and exposure of the cells to cytokines and other polypeptide growth factors in the wound environment. Studies on keratinocytes, as well as results found with other cell types (Welch et al., 1990; Osborn, 1990; Springer, 1990), suggest that integrin receptor modulation plays a central role in wound repair and inflammation.

FIG. 1.

keratinocytess change from a sedentary to migratory lifestyle. This cartoon illustrates one aspect of integrin modulation associated with kératinocyte activation. Skin keratinocytes attach to the basement membrane (BM) by hemidesmosomes (triangles), which contain bp antigens and integrin α5β1 receptors; integrin α6β1 receptors either are not synthesized or are degraded inside the cells. After wounding, keratinocytes migrate on fibronectin (FN) using α5β1 integrin receptors (closed squares) now expressed at the cell surface.

FIG. 1.

keratinocytess change from a sedentary to migratory lifestyle. This cartoon illustrates one aspect of integrin modulation associated with kératinocyte activation. Skin keratinocytes attach to the basement membrane (BM) by hemidesmosomes (triangles), which contain bp antigens and integrin α5β1 receptors; integrin α6β1 receptors either are not synthesized or are degraded inside the cells. After wounding, keratinocytes migrate on fibronectin (FN) using α5β1 integrin receptors (closed squares) now expressed at the cell surface.

Drs. William Snell and Richard Anderson made helpful comments and suggestions regarding this manuscript. The research was supported by NIH grants CA14609 and GM31321.

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