Senior Researcher Brexogen Inc., Seoul-t'ukpyolsi, Republic of Korea
Abstract: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune dysregulation, primarily driven by T helper 2 (Th2) cytokines, leading to severe pruritus, eczematous lesions, and impaired skin barrier function. Despite advancements in targeted therapies, achieving long-term efficacy with minimal side effects remains challenging. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have emerged as promising therapeutic agents due to their immunomodulatory and regenerative properties. To enhance their therapeutic potential, we primed MSCs with interferon-γ (IFN-γ) to generate IFN-γ-stimulated MSC-derived EVs (IFN-γ-MSC-EVs), which exhibit enhanced anti-inflammatory and immunoregulatory functions. Using both in vivo and in vitro AD models, we demonstrated that IFN-γ-MSC-EVs effectively mitigated AD pathology by reducing inflammatory and mast cell infiltration while downregulating Th2 cytokine receptors, including IL-4Rα and IL-13Rα1, along with their associated downstream signaling pathways. Notably, IFN-γ-MSC-EVs significantly alleviated key AD symptoms, including pruritus, transepidermal water loss (TEWL), and skin thickening, while systemically suppressing Th2-related markers in serum. Mechanistically, IFN-γ-MSC-EVs were enriched with immunomodulatory proteins and miRNAs, particularly heat shock protein 70 (HSP70) and miR-22-3p, which contributed to the suppression of Th2 cytokine receptor expression and downstream signaling, ultimately restoring immune balance and promoting skin homeostasis. These findings highlight that IFN-γ-MSC-EVs not only attenuate Th2-driven immune responses but also enhance skin regeneration. Our study suggests that IFN-γ-MSC-EVs represent a promising stem cell-derived therapy for AD and warrant further investigation to evaluate their long-term clinical efficacy.
