Shin Kyong-Oh, Lee Jun Ho, Chae Seungwoo, Goto Karin, An Hahyun, Wakefield Joan S, Ha Dae Hyun, Lee Healim, Lee Kyojin, Lee Hyunju, Shin Ella, Kang Min Ji, Lee Sinhee, Uchida Yoshikazu, Cho Byong Seung, Park Kyungho
Department of Food Science and Nutrition, Convergence Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon, Republic of Korea.
LaSS Lipid Institute (LLI), LaSS Inc., Chuncheon, Republic of Korea.
J Extracell Vesicles. 2025 Jul;14(7):e70121. doi: 10.1002/jev2.70121.
Epidermal permeability barrier defects are associated with several skin diseases, including atopic dermatitis (AD). Using an AD mouse model, we previously demonstrated that topically administered small extracellular vesicles (sEVs) (prepared following the International Society of Extracellular Vesicles recommendations) from human adipose tissue-derived mesenchymal stem cells (ASC) ameliorate skin inflammation and normalize barrier function in parallel with increased ceramide (a key barrier lipid) production. To elucidate how ASC-sEVs alleviate these AD skin abnormalities, we characterized lipids and ceramide metabolic enzymes in ASC-sEVs versus donor ASCs. Our study revealed that free fatty acid, ceramide, and sphingomyelin are enriched in ASC-sEVs versus donor ASCs, while the synthetic enzymes of ceramide (and acidic sphingomyelinase), and sphingosine-1-phosphate (sphingosine kinase) are significantly higher in ASC-sEVs versus donor ASCs. Conversely, ceramide (ceramidase), and sphingosine-1-phosphate hydrolytic enzymes (sphingosine-1-phosphate lyase and sphingosine-1-phosphate phosphatase) are lower in ASC-sEVs, suggesting that ceramide and sphingosine-1-phosphate levels could elevate in cells that receive ASC-sEVs. ASC-sEV-mediated increases in sphingosine-1-phosphate suppress pro-inflammatory cytokine production in AD-model human keratinocytes. Additionally, keratinocyte differentiation, which is required for a competent epidermal permeability barrier, was restored in AD-model human keratinocytes treated with ASC-sEVs. Taken together, cells that endocytose ASC-sEVs can normalize epidermal permeability barrier function as well as alleviate inflammation by stimulating a sphingosine-1-phosphate signalling pathway.
表皮通透性屏障缺陷与多种皮肤疾病相关，包括特应性皮炎（AD）。我们之前使用AD小鼠模型证明，按照国际细胞外囊泡协会的建议制备的、局部施用的源自人脂肪组织间充质干细胞（ASC）的小细胞外囊泡（sEVs）可改善皮肤炎症并使屏障功能正常化，同时增加神经酰胺（一种关键的屏障脂质）的产生。为了阐明ASC-sEVs如何减轻这些AD皮肤异常，我们对ASC-sEVs与供体ASC中的脂质和神经酰胺代谢酶进行了表征。我们的研究表明，与供体ASC相比，游离脂肪酸、神经酰胺和鞘磷脂在ASC-sEVs中富集，而神经酰胺（和酸性鞘磷脂酶）以及鞘氨醇-1-磷酸（鞘氨醇激酶）的合成酶在ASC-sEVs中显著高于供体ASC。相反，神经酰胺（神经酰胺酶）以及鞘氨醇-1-磷酸水解酶（鞘氨醇-1-磷酸裂解酶和鞘氨醇-1-磷酸磷酸酶）在ASC-sEVs中较低，这表明在接受ASC-sEVs的细胞中神经酰胺和鞘氨醇-1-磷酸水平可能升高。ASC-sEV介导的鞘氨醇-1-磷酸增加可抑制AD模型人角质形成细胞中促炎细胞因子的产生。此外，在用ASC-sEVs处理的AD模型人角质形成细胞中，具有正常功能的表皮通透性屏障所需的角质形成细胞分化得以恢复。综上所述，内吞ASC-sEVs的细胞可通过刺激鞘氨醇-1-磷酸信号通路使表皮通透性屏障功能正常化并减轻炎症。
