Hyaluronan in Wound Healing

It was established long ago that the concentration of hyaluronan increases very rapidly in experimental skin wounds (3). Biochemical assays on experimental wounds indicated that hyaluronan reached its peak concentration 3 days after the wound and started to decline before the peaks of proteoglycans and collagen were reached. It was generally accepted that hyaluronan provides a temporary matrix for the migration of inflammatory cells and proliferation of fibroblasts in the connective tissue, but the contribution of epithelial cells was not considered (3).

More recently, hyaluronan was found to be abundant in the migrating cells of wounded human oral epithelium and in cells flanking the wound site (48), suggesting that the epithelial cells undergo a similar upregulation of hyaluronan synthesis. Experiments in our laboratory have shown that this is even more obvious in the mouse epidermis injured by tape stripping of the epidermis. The epidermis of the adult mouse, containing a relatively weak signal for hyaluronan, undergoes a major activation of hyaluronan synthesis in and around the wounded epidermis (Fig. 1f,g), and this is also detectable in an ELISA assay. This is due to the elevated levels of mRNA for the hyaluronan synthases Has2 and Has3 in keratinocytes isolated from the wound area. Interestingly, the RT-PCRs also showed a parallel induction of CD44 mRNA and a corresponding augmentation of CD44 protein, as detected by immunohistochemistry. The importance of the hyaluronan response in the epidermal keratinocytes was stressed by the finding that mice with inhibited epidermal CD44 expression showed an attenuated response to mitogens (49). In vitro, monolayer cultures of CD44—/— keratinocytes maintain less hyaluronan on their surface and migrate slower into a scratch wound introduced into a confluent culture (Tammi et al., unpublished data). Furthermore, overexpression of Has2 increase the migration of keratinocytes in an in vitro wounding assay, while suppression of Has2 by transfection of antisense Has2 gene reduces their mobility (14). There are also in vivo experiments in which application of hyaluronan enhances skin wound healing (50). Upregulation of hyaluronan synthesis and Has2 expression is also essential for wound healing of the mesothelial lining cells of the peritoneal cavity (51). Hyaluronan is thus an important factor in the normal epithelial wound healing process.

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