Induction of a Regenerative State in Hair Follicle Stem Cells by Helium Plasma-Activated Medium Through Coordinated Regulation of Regenerative Programs

Abstract Hair follicle stem cells (HFSCs) are central regulators of hair follicle regeneration and tissue repair, requiring coordinated control of stem-cell activation, migratory responsiveness, and epithelial plasticity. Plasma-activated media have emerged as promising bioactive platforms for regenerative applications through the controlled delivery of reactive oxygen and nitrogen species. In this study, the biological effects of helium plasma-activated medium (He-PAM) on HFSCs were evaluated using functional and molecular analyses. Cell metabolic and migratory activity were assessed alongside the expression of genes associated with regenerative activation (RUNX1, LGR4, and CCND1), migratory competence (CXCR4), and epithelial plasticity (SNAI1 and OVOL2). The selected He-PAM significantly enhanced HFSCs metabolic activity and migration while inducing coordinated transcriptional changes across all three biological programs. Increased expression of RUNX1, LGR4, and CCND1 was associated with regenerative activation, CXCR4 upregulation supported enhanced migratory responsiveness, and the concurrent induction of SNAI1 and OVOL2 was consistent with a transcriptional pattern associated with epithelial plasticity. Collectively, these findings indicate that He-PAM promotes a regenerative-response profile in HFSCs characterized by coordinated regenerative activation, migratory competence, and epithelial plasticity, highlighting its potential as a plasma-based strategy for hair follicle regeneration and broader regenerative medicine application.