Expression of WAVEs, the WASP (Wiskott-Aldrich syndrome protein) family of verprolin homologous proteins in human wound tissues and the biological influence on human keratinocytes

Abstract

WAVEs (Wiskott-Aldrich syndrome protein family verprolin homologs) regulate actin polymerization and influence cellular motility. Here, we investigated the pattern of expression of WAVE-1, WAVE-2, and WAVE-3, in a cohort of human wound tissues together with normal skins and evaluated the role of these molecules in the reepithelialization and migration of keratinocytes. It was shown that there was a significant reduction of the WAVE-3 transcripts in chronic wound tissues, when compared with normal skin and acute wound tissue (p=0.002). Marginal reduction of the WAVE-1 and WAVE-2 transcripts in chronic wounds were also seen. Immunohistochemical analysis showed a significant reduction of all three WAVE proteins in chronic wound tissues in comparison with the acute. We created in vitro cell models using keratinocytes in which we overexpressed WAVE-2, and knocked down the expression of WAVE-1 and WAVE-3. Using ECIS assay, it was shown that knocking down WAVE-3 had a significant effect on the migration and reepithelialization of keratinocytes and that overexpression of WAVE-2 also increased the migration of keratinocytes. We further demonstrated that the impact of WAVE on cell migration was independent upon the PLCg and ERK pathways, but in the downstream requires PI3K pathway and ROCK pathways. In conclusion, the WAVE family proteins are essential for the reepithelialization of keratinocytes. Aberrant expression of WAVEs is linked to the healing process of clinical wounds and loss of WAVE-3 is a particular indicator of an abnormally healing wound. The WAVE proteins have a significant predicative and therapeutic value in wound healing.