Non-thermal atmospheric pressure plasma (NTAPP) has been reported to induce wound healing, activation of immune cells, and proliferation of mesoderm-derived adult stem cells in human. However, the mechanism by which NTAPP activates these physiological effects is poorly understood. Here, we examined whole genome expression profiles of adipose tissue-derived stem cells (ASCs), the proliferation of which is induced by NTAPP. NTAPP upregulated the expression of genes for
cytokine and
growth factor, but downregulated genes in apoptotic pathways. When ASCs were treated with NTAPP in the presence of a
nitric oxide (NO) scavenger, the expression of various
cytokines and
growth factors decreased, suggesting that NO is primarily responsible for the enhanced
cytokine and
growth factor expression induced by NTAPP. Increased
histone deacetyl
transferase 1 (HDAC1) and decreased acetylated
histone 3 were detected in NTAPP-treated ASCs. Similarly, ASCs pre-treated with HDAC, DNA methylation, or
histone methylation inhibitors had reduced expression of
cytokines and
growth factors after NTAPP treatment. Taken together, these results strongly suggest that NTAPP induces epigenetic modifications that activate the expression of
cytokines and
growth factors, explaining how NTAPP acts as an efficient tool in regenerative medicine to stimulate stem cell proliferation, to activate immune cells, and to recover
wounds.