A proposed pathway for small extracellular vesicles derived from human adipose tissue-derived mesenchymal stem cells to ameliorate atopic dermatitis-like skin inflammation

Summary: Abstract Body: Epidermal permeability barrier defects are associated with atopic dermatitis (AD). Using an AD mouse model, we previously showed that topically administered small extracellular vesicles derived from human adipocyte stem cells (sEV) ameliorate skin inflammation and normalize barrier function in parallel with increased ceramide (a key barrier lipid) production. To elucidate how sEV alleviates these AD skin abnormalities, we characterized lipids and ceramide metabolic enzymes in sEV vs. donor adipose tissue-derived mesenchymal stem cells. Free fatty acid, ceramide and sphingomyelin, and ceramide synthetic enzymes (serine palmitoyl transferase and sphingomyelinase) and sphingosine-1-phosphate (S1P) (sphingosine kinase) are enriched, and conversely, ceramide (ceramidase) and S1P-hydrolytic enzymes (S1P lyase and S1P phosphatase) are low in sEV vs. donor cells. Thus, ceramide and S1P levels could raise in cells that receive sEV. Next, we found that sEV mediated increases in S1P suppresses pro-inflammatory cytokine production in AD-model keratinocytes (induced by TNFα/IFNγ) (AD-KC). Additionally, decreased keratinocyte (KC) differentiation, assessed by keratin 10, filaggrin and involucrin mRNA expression in AD-KC, was restored by sEV. Blocking S1P synthesis both attenuated restoration of KC differentiation and suppressed basal KC differentiation. Thus, the S1P-mediated pathway should account for KC differentiation, as well as sEV-driven normalization of KC differentiation. In conclusion, cells which endocytose sEV can normalize epidermal permeability barrier function, as well as ameliorate inflammation by stimulating the S1P signaling pathway. Kyong-Oh Shin^{1, 2}, Jun Ho Lee⁴, Seungwoo Chae¹, Karin Goto¹, Hahyun An¹, Joan S. Wakefield³, Dae Hyun Ha⁴, Healim Lee⁴, Kyojin Lee⁴, Hyunju Lee⁴, Ella Shin⁴, Yoshikazu Uchida¹, Byong Seung Cho⁴, Kyungho Park¹ 1. Hallym University, Chuncheon-si, Gangwon-do, Korea (the Republic of). 2. LaSS Inc, Chuncheon, Korea (the Republic of). 3. University of California San Francisco School of Medicine, San Francisco, CA, United States. 4. ExoCoBio Inc, Seoul, Korea (the Republic of). Epidermal Structure and Barrier Function