Abstract
Bicellular tight junctions are multiprotein complexes that are required for maintenance of barrier function and fence function in epithelial tissues. Wound healing in the oral cavity leads to minimal scar formation compared to the skin, and the precise mechanisms for this regenerative response remain to be elucidated. We hypothesized that oral and skin tissues express a different tight junction repertoire both at baseline and during the wound healing response, and that these molecules may be critical to the differential repair between the two tissues. We re-analyzed a mouse skin and palate epithelium microarray dataset to identify the tight junction repertoire of these tissue types. We then re-analyzed a skin and tongue wound healing microarray dataset to see how expression levels of tight junction genes change over time in response to injury. We performed in vitro scratch assays on human oral and skin keratinocyte cell lines to assay for tight junction expression over time, tight junction expression in response to lipopolysaccharide and histamine treatment, and the effects of siRNA knockdown of claudin 1 or occludin on migration and proliferation. Our data showed that oral and skin epithelium expressed different tight junction genes at baseline and during the wound healing response. Knockdown of claudin 1 or occludin led to changes in proliferation and migration in human skin keratinocytes but not oral keratinocytes. Furthermore, we also showed that skin keratinocytes were more permeable than oral keratinocytes upon histamine treatment. In conclusion, this study highlights a specific subset of functional tight junction genes that are differentially expressed between the oral and skin tissues, which may contribute to the mechanisms leading to distinct healing phenotypes in response to injury in the two tissues.
Highlights
Wound healing is a complex process that occurs across four overlapping stages: hemostasis, inflammation, proliferation, and remodeling
We found 3/27 (11%) tight junctions (TJs) genes to be upregulated (Cldn2, Cldn13, Cldn15) and 7/27 (26%) downregulated (Cldn4, Cldn5, Cldn10, Jam1, Jam2, Ocln, ZO2), and found Jam3 to be both up- and downregulated over time when compared to baseline expression levels
ZO1, ZO3, and Ocln had differential healing responses in skin and tongue and were included in subsequent in vitro analyses. These results demonstrate that TJ genes in oral and skin tissues are differentially regulated in response to wounding, suggesting that TJ composition may play a role in the differential healing response between these tissues
Summary
Wound healing is a complex process that occurs across four overlapping stages: hemostasis, inflammation, proliferation, and remodeling These stages involve multiple cell types that are required to repair and regenerate the affected tissue including fibroblasts, keratinocytes, adipocytes, endothelial cells, and various immune cells. Some histological differences include the presence of hair follicles, sweat glands, and sebaceous glands in skin, while the tongue has taste buds. Despite these differences, both skin and oral tissues are regularly exposed to hazardous conditions such as allergens, poisons, injury/trauma (lacerations or surgical procedures), pathogens (bacteria, viruses and parasites) or temperature changes, which can result in disruption of tissue homeostasis and lead to pathologies. Many factors are responsible for the differential healing outcomes between these two tissues including dissimilar environments and structural variations, intrinsic differences in the unwounded tissues and their differential transcriptomic response to injury are probably the core factors [3,4,8,9,10]
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