Gas plasma therapy of murine and human diabetic wounds is associated with junctional and hippo signaling and oxidative protein modifications

Impaired diabetic wound healing is characterized by delayed tissue repair due to compromised immune function, reduced angiogenesis and blood flow, and decreased levels of essential growth factors. Gas plasma treatment is an emerging therapeutic approach in redox biology, characterized by its ability to modulate biological processes at different stages of tissue repair. This study examined the wound healing process in a preclinical mouse model of type 2 diabetes (T2DM). Repeated exposure to medical gas plasma has been demonstrated to improve microcirculatory parameters, including superficial tissue oxygenation. Consequently, an optimal wound environment is created. Regulating the interplay between proliferation, the balance of apoptotic pathways, and reactive species generated by gas plasma is critical for several cellular processes. This study revealed that the Hippo signaling pathway and yes-associated protein (YAP) activity play crucial roles in this process. Specifically, these mechanisms were observed to facilitate stage-specific cellular responses in diabetic wounds, significantly affecting the survival of skin cell types. Gas plasma stimulates various biological processes, including cell migration, granulation tissue formation, and collagen synthesis. This stimulation occurs through the remodeling of focal adhesions, the restoration of proper extracellular matrix (ECM) architecture, and the regulation of intercellular junctional structures (e.g., tight, adherens, and gap junctions). Mass spectrometry analysis of gas plasma-treated human wounds revealed that 6 % of the identified proteins had undergone oxidative post-translational modifications, suggesting a link between gas plasma-accelerated healing responses and these modifications. These diverse effects highlight the potential of medical gas plasma as a versatile tool for improving wound management and tissue regeneration in diabetes.