YAP/TAZ, beta-catenin, and TGFb pathway activation in medical plasma-induced wound healing in diabetic mice.

ABSTRACT

INTRODUCTION: Hippo is a signaling pathway that is evolutionarily conserved and plays critical roles in wound healing and tissue regeneration. Disruption of the transcriptional activity of both Hippo-associated factors, the yes-associated protein (YAP), and the transcriptional co-activator with PDZ binding motif (TAZ) has been associated with cardiovascular diseases, fibrosis, and cancer. This makes the Hippo pathway an appealing target for therapeutic interventions. OBJECTIVES: Prior research has indicated that medical gas plasma promotes wound healing by delivering a combination of reactive species directly to the affected areas. However, the involvement of YAP/TAZ and other signaling pathways in diabetic wound healing remains unexplored. METHODS: To this extent, ear wounds were generated and treated with gas plasma in streptozotocin (STZ)-induced diabetic mice. Transcriptome profiling at two wound healing stages (days 9 and 20 post-wounding) was performed in female and male mice. Additionally, we employed gene and protein expression analyses, utilizing immunohistological and -chemical staining of various targets as well as quantitative PCR and Western blot analysis. RESULTS: Gas plasma treatment accelerated healing by increasing re-epithelialization and modifying extracellular matrix components. Transcriptomic profiling charting the major alterations in gene expression following plasma treatment was followed by a validation of several targets using transcriptional and translational quantification as well as localization analyses. CONCLUSION: Our study evaluated the cellular regulation of essential targets of the Hippo and related pathways such as YAP/TAZ, ß-catenin, tumor growth factor ß, and oxidative stress signaling after plasma treatment. The activation of genes, pathways, and their regulators is an attractive therapeutic aim for a therapeutic intervention in dermal skin repair in diabetic diseases using medical gas plasmas.