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Histatins are the major wound-closure stimulating factors in human saliva as identified in a cell culture assay

Menno J. Oudhoff^*,1, Jan G. M. Bolscher^*, Kamran Nazmi^*, Hakan Kalay, Wim van 't Hof^*, Arie V. Nieuw Amerongen^* and Enno C. I. Veerman^*

^* Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands; and

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands

¹Correspondence: Academic Centre for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Department of Oral Biochemistry, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail: mj.oudhoff{at}vumc.nl

Wounds in the oral cavity heal much faster than skin lesions. Among other factors, saliva is generally assumed to be of relevance to this feature. Rodent saliva contains large amounts of growth factors such as epidermal growth factor (EGF) and nerve growth factor (NGF). In humans, however, the identity of the involved compounds has remained elusive, especially since EGF and NGF concentrations are 100,000 times lower than those in rodent saliva. Using an in vitro model for wound closure, we examined the properties of human saliva and the fractions that were obtained from saliva by high-performance liquid chromotography (HPLC) separation. We identified histatin 1 (Hst1) and histatin 2 (Hst2) as major wound-closing factors in human saliva. In contrast, the D-enantiomer of Hst2 did not induce wound closure, indicating stereospecific activation. Furthermore, histatins were actively internalized by epithelial cells and specifically used the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway, thereby enhancing epithelial migration. This study demonstrates that members of the histatin family, which up to now were implicated in the antifungal weaponry of saliva, exert a novel function that likely is relevant for oral wound healing.—Oudhoff, M. J., Bolscher, J. G. M., Nazmi, K., Kalay, H., van 't Hof, W., Nieuw Amerongen, A. V., Veerman, E. C. I. Histatins are the major wound-closure stimulating factors in human saliva as identified in a cell culture assay.

Key Words: cell migration • ERK1/2 • antimicrobial peptides • epithelial cells • Candida albicans