Human Epithelial Protein SLURP-2 as a Prototype of Drugs for Wound Healing

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Abstract
Objective: Wound healing is a complex process based on the regulation of proliferation and migration of epithelial cells. Chronic wounds are characterized by increased proliferation and decreased epidermal cell migration. The human secreted protein SLURP-2 regulates the growth and differentiation of epithelial cells. It was previously shown that the targets of SLURP-2 are nicotinic acetylcholine receptors (nAChRs) of different types, as well as muscarinic acetylcholine receptors involved in the regulation of epithelial cell homeostasis. Methods: In this study, we investigated the effect of a recombinant analog of the human protein SLURP-2 and its mutant variants on viability and migration of oral keratinocytes in a wound healing test. The findings were analyzed in comparison with the effect of proteins on the ionotropic activity of the α7-nAChR channel expressed in Xenopus laevis oocytes. Results and Discussion: In this work, we found that acceleration of keratinocyte migration upon incubation with SLURP-2 is mediated by α7-nAChR. Using alanine scanning mutagenesis, we showed that the R20A mutation of the SLURP-2 molecule enhances the inhibitory activity of SLURP-2 toward α7-nAChR and leads to a greater stimulation of Het-1A keratinocyte migration and suppresses the proliferation of Het-1A cells. At the same time, other SLURP-2 mutations inhibit α7-nAChR and reduce the proliferation and migration of keratinocytes. Conclusions: New information about the epitopes of the SLURP-2 molecule, the replacement of which can lead to a targeted change in the biological activity of SLURP-2 was obtained. Further study of ability of regulation of SLURP-2 activity may be useful for a design of new drugs that stimulate wound healing.

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