The Thermosensitive TRPV3 Channel Contributes to Rapid Wound Healing in Oral Epithelia

The oral cavity provides an entrance to the alimentary tract and serves as a protective barrier against a drastic variation of stimuli from food and drink. The oral mucosa is susceptible to injury because of its location; nonetheless, it has faster wound healing than the skin and less scar formation. However, the molecular pathways that regulate this wound healing are still unclear. Transient receptor potential vanilloid 3 (TRPV3), a member of non-selective cation channel, can be activated by warm-temperature (>33°C) and chemicals such as herb ingredients. TRPV3 is known to be expressed in skin keratinocytes and also implicated in temperature sensation (Ref.1-3). Furthermore, it has been reported that TRPV3 regulates epidermal growth factor receptor (EGFR) signaling in the skin keratinocytes (Ref.4).

Here we show that Trpv3 mRNA was the most highly expressed TRP channel in the oral epithelia of C57BL/6 mice. TRPV3 was expressed from the prickle to the basal cell layers, a site of epithelial proliferation, but was not detectable in keratinized layers. TRPV3 agonist cocktails or heat stimuli significantly increased the intracellular Ca²⁺ concentrations in primary oral epithelial cells in wild-type (WT) oral epithelial cells compared with that in TRPV3 gene-deleted (TRPV3KO) cells. In addition, TRPV3 agonists or heat stimulation evoked inward currents at -60mV in the oral epithelial cells from WT and they were decreased in the cells from TRPV3KO or ruthenium red, a broad TRP channel blocker. Next, we investigated the contribution of TRPV3 to wound healing using a molar tooth extraction model and found that oral wound closure was delayed in TRPV3KO mice compared with that in WT mice. Furthermore, Trpv3 mRNA expression in wounded tissues was significantly elevated. Consistent with this finding, strong TRPV3 immunoreactivity was observed in the wound area. Furthermore, the number of Ki67-positive cells in WT primary cultures incubated at 37°C was significantly higher than that at 31°C. This temperature effect was not found in TRPV3KO cells. In addition, the number of 5-ethynyl-2'-deoxyuridine (EdU)-positive cells (actively proliferating cells) was significantly reduced in the oral mucosa in TRPV3KO mice compared with that in WT mice.

In conclusion, we identified TRPV3 as a highly expressed TRP channel in the oral mucosa that plays an essential role in heat-induced oral epithelia proliferation and wound healing. Because TRPV3 is also found in skin, these results suggest that TRPV3 agonists or temperature control might be a novel therapeutic target to promote wound healing in both the oral mucosal and the skin with less scarring.

Statistical comparisons were made using the Student’s t-test or analysis of variance, followed by the Bonferroni-type multiple t test.

References

(1) Xu H, et al. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature. 2002;418(6894):181–186.

(2) Peier AM, et al. A heat-sensitive TRP channel expressed in keratinocytes. Science. 2002;296(5575):2046–2049.

(3) Mandadi S, et al. TRPV3 in keratinocytes transmits temperature information to sensory neurons via ATP. Pflugers Arch. 2009;458(6):1093–1102.

(4) Cheng X, et al. TRP channel regulates EGFR signaling in hair morphogenesis and skin barrier formation. Cell. 2010;141(2):331–343.