Abstract
Reactive species play a pivotal role in orchestrating wound healing responses. They act as secondary messengers and drive redox-signalling pathways that are involved in the homeostatic, inflammatory, proliferative, and remodelling phases of wound healing. The application of Cold Atmospheric Plasma (CAP) to the wound site produces a profusion of short- and long-lived reactive species that have been demonstrated to be effective in promoting wound healing; however, knowledge of the mechanisms underlying CAP-mediated wound healing remains scarce. To address this, an in vitro coculture model was used to study the effects of CAP on wound healing and on paracrine crosstalk between dermal keratinocytes and fibroblasts. Using this coculture model, we observed a stimulatory effect on the migration ability of HaCaT cells that were cocultured with dermal fibroblasts. Additionally, CAP treatment resulted in an upregulation of the HIPPO transcription factor YAP in HaCaTs and fibroblasts. Downstream effectors of the HIPPO signalling pathway (CTGF and Cyr61) were also upregulated in dermal fibroblasts, and the administration of antioxidants could inhibit CAP-mediated wound healing and abrogate the gene expression of the HIPPO downstream effectors. Interestingly, we observed that HaCaT cells exhibited an improved cell migration rate when incubated with CAP-treated fibroblast-conditioned media compared to that observed after incubation with untreated media. An induction of CTGF and Cyr61 secretion was also observed upon CAP treatment in the fibroblast-conditioned media. Finally, exposure to recombinant CTGF and Cyr61 could also significantly improve HaCaT cell migration. In summary, our results validated that CAP activates a regenerative signalling pathway at the onset of wound healing. Additionally, CAP also stimulated a reciprocal communication between dermal fibroblasts and keratinocytes, resulting in improved keratinocyte wound healing in coculture.
Highlights
Cold Atmospheric Plasma (CAP) is an emerging tool of biomedical and clinical importance that controls cellular processes such as wound healing, immunomodulation, cell death, and cancer
For the first time, we demonstrate the activation of the Yes-associated protein (YAP)-Connective Tissue Growth Factor (CTGF)-Cysteine-rich angiogenic protein 61 (Cyr61) axis in response to CAP treatment in a well-characterized human epithelial cell line (HaCaT) and in a human nonneonatal skin fibroblast cell line (GM00637)
There are compelling evidences within the literature indicating that among all the short- and long-lived Reactive oxygen species (ROS) produced by CAP, H2O2 is one of the most stable oxidants produced by kINPen MED [41]
Summary
Cold Atmospheric Plasma (CAP) is an emerging tool of biomedical and clinical importance that controls cellular processes such as wound healing, immunomodulation, cell death, and cancer. The short- and long-lived ROS and RNS produced by CAP are involved in redox signalling in vitro and in vivo. Wound healing involves a coordinated infiltration of dermal cells that is followed by infiltration of immune cells, extracellular matrix deposition, and reepithelization over distinct yet interdependent phases that are regulated by a large number of transcription factors or transcriptional events [2,3,4,5]. ROS are critical secondary messengers that orchestrate wound healing processes by regulating the recruitment of immune cells, angiogenesis, and optimal perfusion of blood at the wound site [6].
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