Epidermal growth factor and keratinocyte growth factor differentially regulate epidermal migration, growth, and differentiation

Various growth factors such as epidermal growth factor and keratinocyte gro wth factor have been reported to promote wound closure and epidermal regene ration. In the present study epidermis reconstructed on de-epidermized derm is was used to investigate the effects of epidermal growth factor and kerat inocyte growth factor on keratinocyte proliferation, migration and differen tiation. Our results show that epidermal growth factor supplemented culture s share many of the features which are observed during regeneration of woun ded epidermis: a thickening of the entire epidermis, an enhanced rate of pr oliferation and migration, and an increase in keratin 6, keratin 16, skin-d erived antileukoproteinase, involucrin and transglutaminase 1 expression. T he increase in transglutaminase 1 protein is accompanied by an increase in the amount of active transglutaminase 1 enzyme. Surprisingly no increase in keratin 17 is observed. Prolonging the culture period for more than two we eks results in rapid senescence and aging of the cultures. In contrast, ker atinocyte growth factor supplemented cultures have a tissue architecture th at is similar to healthy native epidermis and remains unchanged for at leas t 4 weeks of air-exposure. The rate of proliferation and the expression of keratins 6, 16 and 17, skin-derived antileukoproteinase, involucrin and tra nsglutaminase 1 is similar to that found in healthy epidermis and furthermo re keratinocyte migration does not occur. When the culture medium is supple mented with a combination of keratinocyte growth factor and a low concentra tion of epidermal growth factor, skin-derived antileukoproteinase, involucr in and keratins 6, 16 and 17 expression is similar to that found in culture s supplemented with keratinocyte growth factor alone and in healthy epiderm is. Only high transglutaminase 1 expression remains similar to that observe d in cultures supplemented with epidermal growth factor alone. Our results show that the regulation of keratinocyte growth, migration and differentiat ion depends on the availability of these growth factors. Epidermal growth f actor may play a dominant early role in wound healing by stimulating kerati nocyte proliferation and migration while keratinocyte growth factor may pla y a role later in the repair process by stabilizing epidermal turnover and barrier function.